Basic Concepts and Requirements of Galenic Formulations

1. Formulation for Non-Clinical Studies

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Non-clinical safety studies aim to:

• Explore the response at up to maximum achievable doses.
• Detect potential hazards.
• Generate data so a risk assessment can be made.
• Help select the dose for the first clinical studies.
• Suggest ‘markers’ to monitor safety in humans.
• Provide a foundation for specific tests later on.

The safety studies cannot guarantee safety in humans. Also they may not be able to predict how humans respond or to define a mechanism for the induced changes. Safety testing can assess the margins of safety in animal and human data. Considerations for this type of tests are:

• The dose administered,
• The extent and duration of systemic exposure,
• Daily systemic exposure,
• The exposure and identity of metabolites,
• The exposure in target organs.

Safety testing is carried out on the active substance as well as on all related substances, solvents, degradation products, excipients, other active materials and extractives which are part of the final formulation.

2. Formulation for Clinical Studies

Patient acceptance and specific requirements of the active ingredient should be considered in the development of a suitable form of administration. Inactive ingredients (excipients) which can make up most of a medicine’s volume, help carry the active substance in the body. Maize starch or lactose, for example, are used in tablets, while water-oil emulsions are used in ointments.

The administration form also influences how the active substance is absorbed and how available it is. It is therefore important for the medicine’s therapeutic effect. It also determines how the active ingredient enters the body, where and in what dosage it is released, and the time it takes to be absorbed. In addition, the mode of administration must ensure that the patient or health care professional (e.g. doctor or nurse)will be able to dose the medicine safely and handle it easily.

Formulation scientists ensure that the substance can be absorbed by the body and that the therapeutic dose reaches the organ it is meant for (the target organ). Not every active substance is suited to be given as a tablet, and special demands on the form of administration regularly create new challenges for formulation scientists. Examples are injection into the eye, products for inhalation, or orodispersible tablets (tablets that dissolve quickly in the patient's mouth). Innovative pharmaceutical technologies often come into play in this context. Some examples follow.

2.1. Polymers for Continuous Sustained Release

Polymer technologies ensure that the active substance is delivered in the desired dose and in the right place. One example is a tablet with a perforated coating which releases the active ingredient continuously for 24 hours (sustained release). This will save the patient from taking multiple tablets. To produce this tablet, a hole of a precisely defined size is burned with a laser into the coating. The coating is a water-permeable, but not water-soluble polymer membrane. The tablet’s core is divided into two layers. One layer contains the active ingredient, the other a swelling agent. When the tablet is inside the gastrointestinal tract, it will absorb water. This dissolves the active ingredient and causes the tablet to swell. An osmotic pressure is then created inside the tablet, with the result that the dissolved active substance is released at a constant rate through the hole in the coating.

2.2. Solution for poorly soluble medicines

Polymers in medicines formulation are also applied within dosage forms for active substances whose crystals are only slightly soluble in water. Without special processing, such active substances would be excreted by the body unchanged without having any effect. Modern techniques make it possible to embed active substances in water-soluble polymers. In this process the insoluble crystals are split up, and the molecules become  'amorphous' (or shapeless) without a fixed structure. The researchers can now keep the molecules amorphous with the help of polymers. This 'solid solution' of active ingredient and polymer will more easily dissolve in water (and digestive fluids) than the crystals of active substance alone. In many cases, this also leads to a temporary increase in the concentration of dissolved active substance molecules. They can now be absorbed from the intestine into the bloodstream.

2.3. Solutions for Protein Therapeutics

Biologics or biopharmaceuticals can be active substances that are based on proteins, and they are demanding on formulation scientists. If such substances were administered orally, they would be broken down by the digestive fluids in the gastrointestinal tract before they could enter the bloodstream and reach their target site. Biologics are therefore administered by injection into a vein or subcutaneously (under the skin). In order to be injected, the active substance must be available in solution. At the same time, it must be possible to store a medicine over a relatively long period of time if it is to be usable in practice. However, if a biologics is formulated in a ready-to-use solution, there is a risk that the protein molecules will agglomerate (clump together) during prolonged storage and that they will lose their effectiveness. In this case, the formulation scientists must reconcile the need to both preserve efficacy and achieve a long shelf life. In many cases, this challenge can be solved using the technique of freeze-drying (lyophilisation). After this gentle method of drying, the protein molecules often remain stable for at least six months. Shortly before injection the active substance is dissolved in a solution, e.g. in a prefilled syringe.

3. Formulation Testing

The traits or properties of the active substance are evaluated for solubility, stability, particle size, and moisture absorption.

The physical, chemical, microbiological and analytical methodology is developed to test how stable the medicinal product is. Stability testing is done during formulation development. Its purpose is to retain the quality, safety and efficacy of the active substance and the medicinal product. Galenics experts are also responsible for the safe storage of a medicine. They ensure that the content of the active ingredient remains constant, and that the product is chemically stable and maintains its purity throughout its shelf life.

Stability testing helps scientists to understand the effect of temperature, humidity, and packaging. These three elements together determine the shelf-life for the medicinal product. The scientists also retest the period for the active substance, and the storage conditions to be applied to the label. Finally, they determine the primary packing requirements. This activity supports the use of the product in the clinic and for the regulatory submission.

Analytical scientists have more responsibilities. They work to understand the characteristics of the active substance and the medicinal product.  These include the physical properties of the product and its impurity profile. The scientists also produce data and reports to meet testing and regulatory requirements. The methods followed are:

• Physical properties analysis, to understand the characteristics of the active substance and medicinal product.
• High throughput stability analysis, to monitor potency.
• Impurity analysis, to reduce and control related substances from side reactions, genotoxins and degradants, foreign matter or other process impurities.

When it comes to the physical properties of an active substance, the in vivo performance and manufacturability of a formulation are influenced by how the intermediates and the final product are processed. It is necessary to understand both the active substance and the formulation physical properties in order to submit and file a patent. Regulatory authorities are increasingly interested in this area. It is therefore essential to understand the unique physical properties of a medicine throughout its development life cycle.

The formulation and manufacturing processes which are developed to deliver medicinal products for early clinical trials are also important. They should be reliable and follow good manufacturing practice in the entire process, as well as in the scale-up, placebo and reformulation.

Once these factors are fully considered, the formulation can be produced on an industrial scale. It begins with a prototype, and the next step is to reproduce it on a laboratory scale. The scientists then need to transfer the validated analytical methods, formulation and manufacturing processes to processes in manufacturing facilities. The scientists finally reach large-scale production by scaling up the production in several steps at the test facility. The newly developed medicine formulation is initially used and tested in clinical trials (as so-called Investigational Medicinal Product (IMP)) before it can reach the patient as an approved medicine.

4. Good Manufacturing Practice (GMP)

All medicines should be produced according to Good Manufacturing Practice (GMP) before being administered to humans. This accounts also for generic medicines and biosimilars.

GMP guidelines give direction for manufacturing, testing, and quality assurance, in order to ensure that a medicine is safe for use in humans. Many countries have specific laws and regulations that require pharmaceutical and medical device manufacturers to follow GMP procedures. Most regulations are based on guidelines that are agreed to internationally.

The GMP guidelines follow a few basic principles:

• Hygiene: Pharmaceutical manufacturing facilities must be maintained clean.
• Controlled environmental conditions: Cross contamination of a medicinal product from another compound or unrelated particulate matters must be prevented. It could make the medicine unsafe for use in humans.
• Manufacturing processes are clearly defined and controlled:
• All critical processes are validated to ensure they are consistent and compliant with specifications.
• Any changes to processes are evaluated.
• Changes that have an impact on the quality of the medicine are validated as necessary.
• Instructions and procedures are written in clear language that cannot be misunderstood. (Good Documentation Practices - GDP).
• Operators are trained to carry out and document procedures.
• Records are generated, either manually or by instruments: this must be done during manufacture to prove that all the steps in the defined procedures and instructions were actually carried out. Also, that the quantity and quality of the medicine are as expected.
• Deviations are investigated and documented.
• Records of manufacture (including distribution) are retained in full and accessible form. This will make it possible to trace the complete history of a batch.
• The distribution of the medicines minimizes any risk to their quality.
• A system is available so that any batch of medicine can be recalled from sale or supply.
• Complaints about marketed medicines are examined: The causes of quality defects must be  investigated, and appropriate measures taken with respect to the defective medicines. Also to prevent that they recur.

The goal of these good practices is to protect the health of patients and produce good quality medicinal products, medical devices, or active substances. Both in the EU and many other parts of the world it is mandatory to comply with GMP.

Further Reading (optional)

GMP Guidelines:

• European Union (EU): here
• World Health Organisation (WHO): here