Specific standards of GMP

Introduction

The specific standards of GMP refer to the enforceable controls of manufacturing which are in place in order to guarantee that pharmaceutical products are produced and controlled according to quality.

There are several aspects of manufacturing and quality used during the process which include the area, machinery, manpower, documentation, production and quality control. There are some extra Good Manufacturing Practice requirements necessary for sterile manufacturing, which are mentioned in the EU GMP Annex 1 requirements [1].

Which GMP standards apply to pharmaceutical cleanrooms?

gmp cleanroom standards cannot be treated the same as law. The legal obligations come from the regulators of the market while common standards such as ISO 14644 give the testing and classification process [2].

It means that to be compliant with the rules, a facility working within the United States and European ｕｎｉｏｎ must comply with FDA 21 CFR Parts 210 and 211 [3], EU GMP Annex 1 requirements for sterile products [1], and the applicable provisions of PIC/S and WHO [4][5].

The products with active ingredients must obey ICH Q7 rules [6]. Compounding pharmacies are also subject to the requirements of USP <797> [7].

The table below compares principal references, their application, controls required, and the evidence regulators wish to see in inspections.

Regulatory requirements versus cleanroom testing standards

Table 1: GMP and cleanroom standards applicable to manufacturing actions.

Translate applicable requirements into auditable facility specifications

Rules and regulations do not ensure a proper cleanroom. Every requirements specification must lead to supporting evidence for acceptance. Use the checklist below to establish traceability.

For example, for a facility targeting the requirements of EU GMP Annex 1 Grade B, the description should state the maximum amount of particles per cubic metre, at both in-operation and at-rest conditions.

The iso 14644-3 test method also needs to be stated [8]. Otherwise GMP cleanroom qualification turns into pure paperwork instead of verification of engineering.

GMP cleanroom requirements and EU GMP Annex 1 requirements

The requirements of EU GMP Annex 1 actually define four cleanroom grades—A, B, C, and D—for sterile manufacture [1]. Grade A is the critical zone where the product and sterile surfaces come in contact.

Grade B creates the environment for the aseptic operations performed in Grade A. Grades C and D serve the following stages which are not so critical.

Just the classification by particle size is not enough; the contamination control strategy should take into consideration the design of the facility, flow of personnel and transfer of materials.

A common mistake is to consider the certificate of ISO 14644 classification as implying that full GMP compliance is achieved. GMP adds quality system obligations, microbiological monitoring, personnel qualifications and process validation. No particle count can prove those conditions.

Grade-specific particle limits and process applications

Table 2: Particle limits in EU GMP Annex 1 according to the grades [1].

Under both at-rest and working conditions, Grade A allows only 3,520 particles of ≥0.5 µm per cubic metre [1]. Grade B has the same allowable amount at rest but permits up to 352,000 particles in the working state. As for Grades C and D, they allow higher particle concentrations.

The Annex 1 revision does not mention a threshold value of 5.0 µm for Grades A and B anymore [10]. A non-specified threshold does not imply zero particles; it suggests that the standard sets no numerical upper limit.

Layout and contamination controls beyond particle classification

Particle classification is only the first step in maintaining grade in production. Further measures are what allow you to do so. You need to ensure that the path for your personnel, materials, and waste movement does not overlap.

You will have to choose surfaces that are smooth, easy to clean, and compatible with each other in your interior fittings, and use rounded corners where possible [11].

Be clear about the airlock types, transfer methods, and gowning processes you will be implementing depending on the grade of the project in question.

You will also have to consider how cleaning and disinfecting your items will take place, and which contamination control method should be used in that regard.

You will also need to ensure that you take care of the containment protocols for hazardous substances, thus ensuring that you are able to protect your product from being contaminated.

For projects taking place in China, make sure to consider GB 50073 and GB 51110 [12][13].

GMP HVAC system requirements and GMP air filtration requirements

GMP HVAC system requirements entail defining airflow, pressure relationships, temperature, and humidity control so as to protect the products from possible contamination [14]. Remember that GMP requirements refer to performance requirements and not equipment specifications.

Each project must therefore identify its own setpoint according to risk assessment, which should also be confirmed through GMP cleanroom qualification [14][15].

GMP air filtration requirements involve device selection known for its competence across all forms of procedures actually taking place in your project, either in regard to fabricated products or during preservation activities.

HEPA filters for GMP cleanrooms are classified as EN 1822 or ISO 29463 based on efficiency of removal of particles [16]. However, it must be noted that having the filter certificate does not guarantee efficient performance for that particular installation; hence, in-situ integrity testing should be done [8].

Establish airflow patterns pressure relationships and recovery performance

You will need to conduct verification of airflow on a simulated operating basis, and not just an empty room.

Specify HEPA filters for GMP cleanrooms

Data from Deiiang catalogues illustrate the varied choices available. The Combined High Efficiency Filter (H13/H14, EN 1822) uses ultrafine glass fibre media with a separator-free thermoplastic spacer and ABS frame.

At 592 × 592 × 292 mm, it has an airflow of 2,500 m³/h with a media area of 20.04 m², initial resistance ≤200 Pa (H13) or ≤220 Pa (H14), and final resistance 400–600 Pa. All these ratings are catalogue data; actual results depend on the design and qualification of the system.

GMP cleanroom qualification and GMP cleanroom environmental monitoring

The GMP cleanroom qualification of a facility makes sure that it is compliant with specified requirements before normal production starts. GMP cleanroom environmental monitoring ensures that the process remains controlled.

Qualification and monitoring are completely separate functions. Qualification leads up to a project milestone and monitoring is an operational activity. However, both activities must be traceable to written acceptance requirements from the user requirements specification.

ISO 14644-1 covers classification and ISO 14644-2 monitoring, and ISO 14644-3 sets explicit methods of testing [2][8][9]. Each section applies to its own scope. Microbiological monitoring is done based on risk analysis, through setting of alert and action levels based on historical and qualification data [17].

Qualification stages and required test evidence

Routine monitoring limits and contamination investigations

Qualification provides the baseline and monitoring detects any deviation.

• Classification limits and the alert and action limits for monitoring should be differentiated.
• A description of viable and non-viable sampling strategies must be provided as justification.
• Grade A should be monitored during critical operations, with daily monitoring of the iso 5 classification [18].
• Set monitoring levels based on qualification and trend data, typically at the 90th percentile [19].
• Align alert thresholds to the EU GMP Annex 1 requirements for regulatory action limits [17].
• Investigate all monitoring excursions to determine whether they require corrective action.

QA managers are frequently confounded when they detect an excursion and believe an equipment failure has occurred. If this is within the first three months of operation, the most likely cause is a personnel training gap.

The monitoring programme must be able to discern transient personnel-related excursions from systematic HVAC problems. An example seen several times was an excursion at shift change, where all records show it cleared within fifteen minutes, indicating a personnel problem.

Selecting and maintaining Deiiang cleanroom systems against GMP requirements

Deiiang cleanroom systems and air filters are designed and built based on documented compliance requirements, not general marketing claims. The procurement acceptance criteria need to be based on the documented compliance needs of GMP.

These criteria include efficiency class, test method, airflow capacity, pressure drop, and material compatibility.

Component specifications must be differentiated from qualified facility performance. A filter or panel that meets the specifications of a catalogue does not necessarily mean that the cleanroom will also achieve the required qualification.

Procurement evidence for panels modules and filtration equipment

The following notes are based on Deiiang experience with panel and filtration installation.

• Panel marring during installation makes it impossible to clean contamination spots.
• Using the wrong gaskets in filter compartments renders the HEPA filter enclosure useless.
• Misalignment in panel seams will not maintain ventilation and pressure requirements.

In order to avoid the above problems, examine components prior to installation, use proper lifting equipment, and install the panels with trained personnel.

Deiiang provides both MGO and MGO rockwool panels for cleanrooms, in various sizes, including 2 m × 3 m × 3 m, 4 m × 3 m × 3 m, and 6 m × 5 m × 3 m. The effective width of the panels is 1,150 mm, and the thickness can range between 50 mm and 100 mm.

The rockwool density ranges between 60–140 kg/m³ and has a fire-resistance rating of up to 120 minutes. All of the above specifications can be used for procurement records but cannot ｒｅｐｌａｃｅ project-specific qualification.

Project-reported case study linking design targets to qualification results

Frequently Asked Questions

In this section, we will provide answers to some common questions related to QA, engineering, validation, and purchasing regarding the GMP cleanroom system.

What are the specific standards of GMP for pharmaceutical facilities?

The specific standards of GMP for pharmaceutical facilities include FDA 21 CFR Parts 210 and 211, EU GMP Annex 1 requirements, and guidance given by PIC/S and WHO. They take into consideration the design of the facility, the personnel, equipment and documentation, production, and quality assurance. Sterile production adds cleanroom requirements classified in Grades A through D, along with contamination control activities.

Does ISO 14644 certification prove compliance with GMP standards?

ISO 14644 certifies that a cleanroom has achieved a particular level of particle concentration classification at the time of testing. Compliance with GMP standards requires additional quality control systems that include microbiological monitoring, personnel qualifications, and process validation. Cleanroom test results are a good basis for regulatory compliance, but they do not guarantee it, because they must be used as part of the complete strategy.

Do GMP cleanroom requirements prescribe a universal air-change rate?

There is no defined air-change rate in the GMP standards. The air-change rate to be used will be determined by the contamination load resulting from the activity being performed, room use, and how effective recovery needs to be. Qualification will be based on pre-established acceptance criteria and not on a number at random.

Are HEPA filters for GMP cleanrooms required in every manufacturing area?

HEPA filtration is necessary in critical sterile areas, specifically Grade A and B areas. In less critical or non-sterile manufacturing areas, the use of HEPA filtration can be based on risk analysis. A HEPA filter alone does not mean compliance with GMP; it must be part of an approved system with valid integrity testing and monitoring.

How often is GMP cleanroom qualification required?

EU GMP Annex 1 requirements establish the maximum requalification periods for sterile grades: six months for Grade A and B, and twelve months for grade c and D. Requalification has to be performed when significant changes occur, when corrective actions have taken place, or when there are indications of unacceptable monitoring trends. Qualification requirements for non-sterile cleanroom areas can differ depending on a risk assessment.

What documentation should buyers request from a cleanroom equipment supplier?

Documentation requested should refer to specifications with valid test laboratory reports, material records, calibration certificates, and similar evidence. Documentation will include filter efficiency data as well as material certifications. Ultimately, the purchaser is responsible for the proper qualification of the facility; documentation from the provider serves only as support for that process.

References

• [1] EU GMP Annex 1: Manufacture of Sterile Medicinal Products, 2022 revision.
• [2] ISO 14644-1:2015, Cleanrooms and associated controlled environments—Part 1: Classification of air cleanliness by particle concentration.
• [3] FDA 21 CFR Parts 210 and 211, Current Good Manufacturing Practice for Finished Pharmaceuticals.
• [4] PIC/S GMP Guide, Pharmaceutical Inspection Co-operation Scheme.
• [5] WHO GMP for sterile pharmaceutical products, WHO Technical Report Series No. 961, Annex 6.
• [6] ICH Q7, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients.
• [7] USP <797>, Pharmaceutical Compounding—Sterile Preparations.
• [8] ISO 14644-2:2015, Cleanrooms and associated controlled environments—Part 2: Monitoring to provide evidence of cleanroom performance.
• [9] iso 14644-3:2019, Cleanrooms and associated controlled environments—Part 3: Test methods.
• [10] Particle Measuring Systems, Cleanroom Classification Explained: ISO 14644-1:2015 vs EU GMP Annex 1.
• [11] cGMP cleanroom construction requirements, coved corner details, NIH ORF.
• [12] GB 50073-2013, Code for design of clean room.
• [13] GB 51110-2015, Code of construction and quality acceptance of industrial cleanroom.
• [14] EU GMP Annex 1 pressure differential guidance, 10–15 Pa between adjacent grades.
• [15] ISO 14644-3 recovery test method, 100:1 recovery time.
• [16] EN 1822-1:2019, High efficiency air filters (EPA, HEPA and ULPA)—Part 1: Classification, performance testing, marking.
• [17] USP <1116>, Microbiological Control and Monitoring of Aseptic Processing Environments.
• [18] FDA guidance, Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice.
• [19] EU GMP Annex 1 environmental monitoring, alert and action limit guidance.