General conditions and legal requirements for formulation development

Here you will find answers to the following questions:

§  Why must GMP principles already be applied in the development phase?

§  Which GMP rules must be applied in pharmaceutical development?

§  What is the possible structure of a quality assurance system for pharmaceutical development?

§  What basic conditions make it difficult to apply GMP principles in development?

It may sound like a contradiction in terms that certain quality standards must already be applied in the research and development phase of pharmaceuticals: Is this not a hindrance to the freedom and creativity of our scientists if each idea has to be formally documented, checked, approved, and archived? Does this not cause unnecessary extension of development times and hence drive development costs upwards?

To answer these questions, we have to differentiate as follows:

§  Each medicinal product intended for use in humans must be manufactured and tested in accordance with GMP, regardless of whether it is a registered or approved commercial preparation, or a development or comparator drug for a clinical trial. Recent regulations specifically cover clinical trials and clinical samples, for example the EU-GMP Directive 2003/94/EC (8.10.2003), the 1st revision of Annex 13 of the EU-GMP Guideline (2003), the 14th amendment to the German law on the regulation of pharmaceuticals (AMG-Novelle) (2005), the German GCP regulation (2004), the AMWHV (= new version of the German PharmBetrV of 2006 on the regulation of pharmaceutical manufacturing), the EMEA Guideline on the Requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials CHMP/QWP/185401/2004, the PIC/S-Aide-Mémoire GMP Particularities in the manufacture of medicinal products to be used in clinical trials on human subjects (Dec. 2005), and the draft guidance published by the FDA in January 2006 IND-Approaches to complying with cGMP during Phase 1 which, once finalised, will replace the former Guideline on the Preparation of Investigational Drug Products (1991). (The draft supplementation to the CFR, section § 210.2 (c), published simultaneously, was already withdrawn in May 2006.)
With these requirements, legislators are protecting both consumers (patients) and healthy volunteers who participate in clinical trials. However, legislators do concede that GMP principles should be applied in a manner "appropriate to the development stage of a drug product".

§  In the development phase even the manufacturing and testing of medicinal products that are not used in humans is not free from legal regulations. Depending on the aim of the studies in which the experimental medicinal products are used, certain regulations must still be observed. For example, if the data is to be used as evidence of toxicological safety or environmental compatibility (ecological toxicology), the GLP guidelines must be complied with (see chapter 16.C Interfaces to GLP and GCP). If data is to be used to prove stability (stability testing, see chapter 16.B.3 Manufacturing and testing of stability samples and chapter 14.G Stability testing), the GMP guidelines must be complied with.

§  Only experiments for the sole purpose of establishing a formulation, technical development, or process optimisation, are not subject to regulatory requirements. In these cases, it is still advisable to maintain a minimum level of documentation and experimental planning. This is the only way to ensure that results obtained are trustworthy and reproducible, and can be used, for example, as a basis for a planned process change (see chapter 16.E Documentation and recording of changes during development). To ensure the reproducibility of this type of technical data, the measuring equipment used must be calibrated, for example, although solely from a technical scientific perspective rather than as a regulatory requirement.

§  Quality standards are particularly important in development, since the later optimisation, validation, and production are based on the data and findings obtained at this stage. Development therefore becomes virtually "birth of quality", as opposed to a "root of all evil". Poorly developed and hence irreproducible formulations or procedures always cause considerable costs and time delays in later development phases. A step regarded as time-saving in early development therefore does not always turn out as such in the end.
Not least, quality standards in development are important because the data obtained during these phases is relevant for the subsequent marketing authorisation of the medicinal product (see chapter 16.F Development report).

Nonetheless, the concerns mentioned initially should not be completely dismissed. A quality assurance system for development must be adjusted to suit the specific requirements of development, to prevent every innovation from being nipped in the bud. Difficulties usually arise when existing quality assurance systems - which are based on the requirements of pharmaceutical production - are applied in exactly the same way to development products. This often happens due to the aim of harmonising internal processes and the well-meaning intention to establish only one quality standard within the company. However, this practice is far beyond requirements - even authorities define clear differences for the application of GMP in development compared to routine production. Both Annex 13 of the EU-GMP Guideline (chapter C.6.13 Annex 13 - Revision 1 Manufacture of Investigational Medicinal Products), and the FDA Guideline on the preparation of investigational new drug products specify, for example, that GMP principles should be applied as appropriate to the development stage of a drug product.

This should be taken into account when designing the quality management system for development. Depending on the company structure, organisation and size, it can be practical to

§  establish a separate quality unit and separate processes for R&D within quality assurance, which take into account the specific requirements of development, as well as (where possible and practical) aiming towards consistency with the quality assurance system in production.

§  keep R & D as an independent organisation equipped with its own GMP unit, GMP manager, or even its own separate quality assurance.

Since there are barely any regulatory specifications that deal with quality management specifically in the development phase, at the end of 2003, the ICH decided to develop and coordinate its own guideline under the title ICH Q8 Pharmaceutical Development - Quality by Design, to be subsequently implemented in the USA, Europe and Japan.

Regardless of how the problem is solved from an organisational perspective, it is important to develop a consciousness among all staff that there are not "two different standards" running alongside each other. Neither R & D simply operates in a "GMP-light" nor "GMP-like" manner. Similarly, the aim is not to exploit any leeway in legal regulations, but rather to perform sufficient quality assurance during the development phase to guarantee the safety of patients, volunteers, and data while also still allowing development to take place - and at an affordable cost!

In addition to increasing reductions in development time, the application of GMP principles is further complicated by extremely complex, often short-term or one-off activities during the pharmaceutical development process (see chapter 16.B Development phases and GMP requirements).

The development process is governed by different basic conditions than routine production:

§  Clinical studies are usually performed with test formulations (for example, capsules), which are not identical to the intended commercial product (for example, tablets). This means that ultimately, two different galenic preparations have to be developed, analyzed, tested for stability, and optimised, sometimes in parallel.

§  The early phases of clinical studies are usually performed using varying dosages of a drug, because clinical research first has to establish the effective and tolerable dosage. For formulation and analytical development, this means that not only must different formulations be developed in parallel, but each formulation also has to be manufactured, tested, and its stability verified in each different dosage.

§  During development, often only small amounts of drug substance are available in case an innovative drug is investigated. The number and batch size of possible experimental approaches is therefore strictly limited as a consequence.

§  The synthesis of new drug substances is usually improved and optimised in parallel with formulation development, which can result in changes in API quality. However, seemingly minor changes can significantly influence the behaviour of the API in processing, or may even alter the physico-chemical properties of the final dosage form. For example, changes in the by-product spectrum or the content of residual solvents (in particular the reduction of impurities) can affect the solubility, dissolution rate, and hence also the absorption of the drug substance in the organism. Recrystallisation from other solvents can result in different crystal modifications with different powder flow behaviour, solubility properties, stability, etc., and which in some circumstances may suddenly confront the formulation scientist with significant problems. Even changing the particle size distribution of the API (for example due to a change in manufacturer) can make processing in accordance with the specified process impossible, thus necessitating a process change (for example, additional milling, classification, or granulation).

§  As soon as long-term clinical studies have started, the supply with clinical samples must be assured as a priority, due to the immense costs of these studies. This means that the developer is strictly limited in terms of time planning, consumption of drug substance and even batch sizes - for cost reasons, these large clinical batches are usually used simultaneously for scale-up and/or process validation, and long-term stability batches. For purely technical experiments, in contrast, there is usually very little material available.

§  Drug products that are intended to be marketed in several countries have to fulfil a diverse range of market requirements, for example, in terms of tablet coating colour, tablet shape, printing of capsules or film tablets, as well as in terms of their primary packaging. However, these issues must be clarified before long-term stability batches are manufactured, since these stability studies for submission purposes have to be performed with the final market formulation in the same primary packaging as forseen for the market.

Summary In pharmaceutical development, GMP rules have to be applied as soon as clinical samples are manufactured or data has to be obtained for marketing authorisation purposes. However, the requirements are graded according to the development stage of the medicinal product. Compliance with quality standards in development is important in order to guarantee the safety of patients or healthy volunteers in clinical studies. However, it is equally important that the data and findings obtained during development are verified, trustworthy, and reproducible, because these form the basis for the production process and the submission file for marketing authorisation. A quality management system needs to be established that takes into account the specific basic requirements of the development stage.