What are the Requirements for the Manufacture of Solid Dosage Forms in Pharmaceutical Production?

As for other dosage forms, the following also applies to the manufacture of oral solid dosage forms (or oral solid dosage forms, OSD): equipment and premises must be suitable, and manufacturing processes must be validated. In addition, the general requirements for production laid down in Chapter 5 of Part I of the EU GMP Guide apply, such as cleanliness, appropriate storage of starting materials, intermediates and finished products, in-process controls, and quarantine of the finished product until release.

In detail, the manufacture of dosage forms such as granules, tablets or capsules is far less tightly regulated by GMP than the manufacture of sterile dosage forms. Nevertheless, quality, safety and efficacy must of course be ensured to the same extent, even if the risk of microbial contamination is much lower and far less critical than for injectables, since solid dosage forms are administered orally and not injected.

A key GMP aspect in the manufacture of solid dosage forms is the prevention of mix-ups/cross-contamination. Here, physical and HVAC separation as well as cleaning validation play a decisive role. Guidance is provided, for example, by the ISPE Baseline Guide on Oral Solid Dosage Forms and by WHO Guidelines:

• Guidelines on heating, ventilation and air-conditioning systems for non-sterile pharmaceutical products (Annex 8, TRS 1010)
• Part 2: Interpretation of Guidelines on heating, ventilation and air-conditioning systems for non-sterile pharmaceutical products (Annex 2, TRS 1019)

Manufacturing equipment

Equipment used for OSD production (e.g. mixers, granulators, dryers, tablet presses, capsule-filling machines, coaters) must be suitable for its intended purpose. This is demonstrated as part of the qualification of this equipment. According to Part I, Chapter 3 of the EU GMP Guide, equipment must be designed and installed in such a way that it is suitable for its intended purpose and allows for easy cleaning, calibration and maintenance.

Similarly, the FDA requires in 21 CFR §§ 211.63-67 that all equipment used in manufacturing and packaging is of appropriate design to fulfil its intended purpose and also facilitates cleaning and maintenance. This, however, applies generally and not specifically to equipment for the manufacture of solid dosage forms. Surfaces in contact with the product must be such that they do not react, release or absorb any substances - i.e. they must not adversely affect the quality of the medicinal product. In addition, equipment and utensils must be cleaned and maintained at appropriate intervals to prevent contamination or malfunction. Written, binding procedures must be in place for all cleaning and maintenance activities and must be strictly followed. This likewise applies generally, regardless of the dosage form.

Premises

In Europe, the EU GMP Guide does not define specific cleanroom classes for the manufacture of solid dosage forms, as is the case for sterile products. Instead, it requires the manufacturer to define an appropriate hygiene level and zoning on the basis of a risk assessment. In practice - particularly in German-speaking countries - it has become common to refer to Annex 1 and extend it with zones E and F. The basis for this was the (now withdrawn) ZLG Aide Mémoire "Inspection of qualification and validation in pharmaceutical manufacture and quality control", which proposed microbiological limits for production areas for non-sterile medicinal products and, "by analogy with Annex 1 of the EU GMP Guide", classified these areas as zone E (manufacture of non-sterile semi-solid and liquid dosage forms) and zone F (manufacture of tablets, capsules and sugar-coated tablets).

For zone F, used for the manufacture of, for example, tablets, the ZLG document defined a warning limit of 500 CFU/m³ and an action limit of 800 CFU/m³ (in operation) and suggested quarterly to annual monitoring. The FDA likewise does not specify fixed cleanroom classes or zone designations for OSD manufacture, but also expects a coherent, risk-based zoning concept with suitable measures to protect against contamination and cross-contamination.

The situation is different in some third countries: for example, Indonesia explicitly defines a Class E for the processing of non-sterile products in its GMP regulations, with specified particle limits, and in other countries (e.g. parts of Asia or the CIS) authorities sometimes expect open product handling to take place at least in areas broadly corresponding to Grade D. In effect, the EU and the USA tend to work with freely definable, risk-based zones (including E/F as an operator concept), whereas some countries specify clear formal classes for non-sterile OSD processes.

A different approach is described in the WHO Guide (Annex 2, TRS 1019, see above). For premises, it defines a three-level system of protection or hygiene that is deliberately simpler than ISO or Annex 1 classes:

• Level 1 covers general areas with normal housekeeping practices, where no activities are carried out that pose an increased risk of microbiological or particulate contamination (e.g. storage areas).
• Level 2 describes "protected areas" in which the product is indirectly protected, for example secondary packaging, certain storage areas or first-stage changing rooms.
• Level 3 comprises "controlled areas", in which product, starting materials or product-contact parts are exposed to the environment - i.e. typical manufacturing steps such as granulation, blending, tabletting, capsule filling, as well as washing and interim storage areas for cleaned parts.

For Level 3, the guide calls for defined and monitored environmental conditions (temperature, relative humidity, particles, and possibly germs), without mandating a specific ISO class

Ventilation and containment concepts

A key element for solid-dosage facilities is the "clean corridor" concept, as also recommended in the WHO Guide (Annex 2, TRS 1019, see above). It is recommended that production areas for solid oral dosage forms be designed such that a clean corridor is maintained at a higher pressure than the adjacent production areas in which particle-generating operations (e.g. tabletting) are carried out. When a door is opened, air then flows from the cleaner corridor into the production areas, not the other way around. In this way, the corridor remains relatively dust-free and acts as a clean buffer zone between production areas and the rest of the facility.

This concept is supported by material and personnel airlocks (MAL, PAL), which are likewise operated with defined pressure differentials and air-change rates. The aim is to retain dust and product particles in their area of origin while at the same time providing safe, defined routes for personnel, materials and equipment, without allowing them to "carry" contamination into other areas.

Cross-contamination - dedicated and multipurpose facilities

A central aspect is the prevention of contamination - both microbiological and, above all, chemical (cross-contamination). This includes suitable HVAC systems with defined air-change rates, pressure cascades (e.g. cleanroom versus surrounding areas), separate personnel and material airlocks, as well as appropriate surfaces and floors.

The best protection against cross-contamination is single-product manufacturing (production of only one product) or the physical segregation of different production lines, so-called dedication (as opposed to "multipurpose"). Dedicated facilities do not necessarily have to be two completely separate buildings, but they do require strict structural and technical segregation (separate areas, separate HVAC systems, separate equipment). It must be ensured structurally (not merely organisationally) that product A cannot contaminate product B (and vice versa).

In answering the question of whether dedication is required or not, the EMA "Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities" is helpful. The guideline introduces the concept of HBEL/PDE (health-based exposure limit/permitted daily exposure) and addresses the question "how much cross-contamination can be tolerated?", since zero contamination does not exist. The guideline explains how a substance-specific limit can be derived by toxicological assessment and regarded as safe. These values are taken into account when establishing the limits to be achieved in cleaning and cleaning validation. In addition, a validated analytical method must be in place that is capable of detecting values at or around this limit. If it can be demonstrated that the required limits are achieved by cleaning before another product is manufactured on, for example, the same equipment, dedication is not strictly required and a multipurpose operation is possible. Products for which no HBEL/PDE can be determined or for which there are no sufficiently sensitive analytical methods must be manufactured in dedicated facilities.For the manufacture of penicillins, cephalosporins and other substances, the US FDA requires dedication.