Construction standards and design key points of GMP purification workshops for Biopharmaceuticals/Pharmaceutical factories

As a biopharmaceutical enterprise, the entire production process must meet GMP standards to ensure the quality of drugs. The GMP purification workshop technology of biopharmaceutical enterprises is one of the main means to ensure the successful implementation of GMP. Then, what knowledge about cleanrooms does a pharmaceutical manufacturing enterprise need to know?

What is the GMP standard and what is its significance?

1.What is the GMP standard

GMP standards are a set of mandatory standards applicable to the pharmaceutical, food and other industries. They require enterprises to meet the hygiene and quality requirements in terms of raw materials, personnel, construction equipment, production processes, packaging and transportation, quality control and other aspects in accordance with relevant national regulations, and form a set of operational norms to help enterprises improve their hygiene environment, promptly identify problems existing in the production process and make improvements. The GMP standard is the most fundamental condition that pharmaceutical processing enterprises must meet.

2.The significance of implementing GMP standards

The quality of drugs is not determined by inspection, but is guaranteed by placing the entire drug production process under scientific, strict and rigorous management and control. Therefore, qualified drugs must meet two conditions: one is that the drugs themselves comply with quality standards, and the other is that the entire production process must conform to GMP. This is precisely the reason why it is mandatory for the production environment of pharmaceutical manufacturing enterprises to meet GMP standards.

Requirements for clean areas in biopharmaceutical workshops

The clean areas in the workshops of biopharmaceutical enterprises are classified into four levels: A, B, C, and D. The main control targets are the number of bacteria and dust particles in the environment. At the same time, regulations are also made for the temperature, humidity, pressure difference, illuminance and noise of the environment. Now let's first understand the relevant requirements for the clean area in the workshop of a biopharmaceutical enterprise.

GMP workshop clean area Cleanliness grade standards

China's GMP (newly revised in 2010) stipulates that to ensure the quality and safety of sterile drugs, the new version of GMP has adopted the latest A, B, C, and D classification standards of the WHO and the European Union in the appendix for sterile drugs, and has put forward specific requirements for the cleanliness level of sterile drug production.

Static: It refers to the state of the cleanroom environment when a cleanroom or clean area is built and the equipment is in place, but there is no personnel activity, no equipment operation, and no production operation is carried out.

Dynamic: The state of the cleanroom environment when the facilities in the cleanroom or clean area operate in the agreed manner, and a specified number of personnel are active, equipment is running, and production operations are carried out in the agreed manner.

Requirements for the working environment in the clean area of GMP workshops

Explanation

➡️ Class A area: high-risk operation areas, such as filling areas, areas for placing rubber stopper barrels, open ampoules, open vials, and areas for aseptic assembly lines or connection operations. Laminar flow operation tables (hoods) are usually used to maintain the environmental conditions of this area.

The laminar flow system must provide uniform air supply in its working area, with an air velocity of 0.36- 0.54M/S (guideline value). There should be data to prove the state of laminar flow and verification is required. In a closed isolation operation area or glove box, unidirectional flow or a lower wind speed can be used.

➡️ B-level area: refers to the background area where high-risk operations such as aseptic preparation and filling are located in the A-level area.

➡️ Zone C and Zone D: These refer to the less important clean operation areas in the process of producing sterile drugs.

➡️ grade A, grade B is equivalent to grade 100. The background environment of grade A is higher and the requirements are stricter.

➡️ Class C is equivalent to class 10,000 and class D is equivalent to class 100,000

The cleanliness level and application scope of GMP workshops

Introduction to the types of GMP cleanrooms in Biopharmaceutical enterprises

1.Turbulent flow

The air enters the GMP purification workshop from the air conditioning unit through the air ducts and the air filters in the clean room, and is returned by the partition wall panels on both sides of the GMP purification workshop or the raised floor. The airflow does not move in a straight line but presents an irregular turbulent or vortex state. This type is suitable for GMP cleanroom grades ranging from 1,000 to 100,000.

Advantages: Simple structure, low system construction cost, easy expansion of clean rooms, and in some special-purpose places, dust-free workbenches can be used in conjunction to improve the grade of clean rooms.

Disadvantage: The fine dust particles caused by turbulence float in the indoor space and are difficult to be discharged, which can easily contaminate the products in the manufacturing process. In addition, if the system stops running and is reactivated, it often takes a considerable amount of time to achieve the required level of cleanliness.

2.Laminar flow

The laminar air flow moves in a uniform straight line. The air enters the room through a filter with a 100% coverage rate and returns through the raised floor or the partition boards on both sides. This type is suitable for use in environments where the GMP cleanroom grade needs to be set at a relatively high level. Generally, its cleanroom grade ranges from Class 1 to 100. Its forms can be divided into two types:

(1) Horizontal laminar flow

Horizontal air is blown out in one direction from the filter and returned by the return air system on the opposite wall. Dust is carried out of the GMP purification workshop in the direction of the wind. Generally, the pollution is more serious on the downstream side.

Advantages: Simple structure, and it can become stable in a short time after operation.

Disadvantages: The construction cost is higher than that of turbulence, and the indoor space is not easy to expand.

(2) Vertical laminar flow type

The ceiling of the GMP purification workshop is completely covered with ULPA filters. The air blows from top to bottom, achieving a high level of cleanliness. Dust generated during the manufacturing process or by the staff can be quickly discharged outdoors without affecting other working areas.

Advantages: Easy to manage, it can reach a stable state within a short time after operation starts, and is not easily affected by the working condition or the operators.

Disadvantages: The construction cost is relatively high, it is difficult to flexibly utilize the space, the ceiling hangers take up a lot of space, and it is rather troublesome to maintain and replace the filters.

3.Composite type

The composite type combines turbulent flow and laminar flow, which can provide locally ultra-clean air.

(1) Clean tunnel: By covering 100% of the production or working area with HEPA or ULPA filters, the cleanliness level can be raised to above grade 10, which can save installation and operation costs. This type requires that the work area of the operators be isolated from the product and machine maintenance to avoid affecting the work and quality during machine maintenance. Most ULSI processes adopt this type. The clean tunnel has two additional advantages: A. It is easy to expand flexibly; B. Maintenance of equipment can be easily carried out in the maintenance area.

(2) Clean pipelines: Surround and purify the automatic production lines that the product process passes through, raising the cleanliness level to over 100. As the products, operators, and dust-generating environments are isolated from each other, a small amount of air supply is sufficient to achieve good cleanliness, which can save energy. Automated production lines that do not require manual labor are most suitable for use. They are applicable to the pharmaceutical, food, and semiconductor industries.

(3) Parallel installation of local clean rooms: Raise the cleanliness level of the product production area in the turbulent flow dust-free room to above 10 to 1000 grades for production use. Clean workbenches, dust-free workshops, clean work sheds, and clean air handling units fall into this category.

4.GMP grade classification for biopharmaceutical workshops

Generally speaking, the clean areas of biopharmaceutical workshops are classified into different grades according to GMP standards, and each grade has its corresponding cleanliness requirements.

We can choose different grades of biopharmaceutical cleanrooms according to different production requirements. The following are the requirements for GMP cleanliness grades in various common clean areas of biopharmaceutical workshops:

(1) Sterile production workshop: The sterile production workshop is used for manufacturing sterile drugs, such as injections, eye drops, etc. Under GMP regulations, the clean areas of such workshops need to meet the highest level of cleanliness grade, usually GMP Grade A.

(2) Biological Preparation workshop: The biological preparation workshop is used for the production of biological drugs, such as antibody drugs, vaccines, etc. The cleanliness level requirements for the clean areas of such workshops may vary depending on the production process, but they usually need to meet at least GMP Grade B.

(3) Cell culture workshop: The cell culture workshop is used for operations related to cell culture, such as cell separation, cell culture, and cell cryopreservation. The cleanliness level requirements for the clean area of this type of workshop may vary depending on the operation, but they usually need to reach at least GMP grade C.

(4) Hazardous Substances Treatment Workshop: The hazardous substances treatment workshop is used for handling hazardous substances, such as radioactive materials and toxic drugs. The cleanliness level requirements for the clean area of such workshops may vary depending on the hazard of the substances and the handling process, but they usually need to meet at least GMP grade D.

5.Layout of GMP pharmaceutical clean workshops

(1) Production area layout

The layout of the production area should conform to the process flow, be compact and reasonable, reduce the detours and back-and-forth of the production process, facilitate the rapid transfer of materials, facilitate production operation and management, and prevent errors and cross-contamination to the greatest extent.

(2) A reasonably sized area

There should be production areas and storage areas commensurate with the production scale. Necessary process equipment should be set up in the production area, and materials unrelated to operations are not allowed to be placed there. The storage area must not be used as a passage for non-local staff.

(3) Configuration of the preparation production workshop

In addition to having rooms for each production process, the formulation production workshop should also be equipped with sufficient production auxiliary rooms, such as temporary storage rooms (areas) for raw and auxiliary materials, weighing rooms, material preparation rooms, temporary storage rooms (areas) for intermediate products, inner packaging materials, etc., washing, drying and storage rooms for tools and turnover containers, and washing, drying and storage rooms for cleaning tools. A washing, sorting and storage room for work clothes is provided, and water-making rooms, air-conditioned purification machine rooms, workshop inspection rooms, etc. are configured as needed.