- Medicine Information and Evidence for Policy > Medicines Policy
- Medicine Access and Rational Use > Rational Use
(2003; 199 pages)
Once a formulation and method of manufacture have been developed, the temptation is to proceed with this design even if stability and/or bioavailability testing show that it is suboptimal. Probably at least a year will have passed by the time bioavailability studies are completed and stability studies produce meaningful long term results, during which time rival manufacturers will have been developing their own products. So how can a manufacturer increase the probability that a particular formulation will be successful in terms of consistent quality and regulatory compliance? Answer by - conducting a thorough review of relevant scientific literature and by undertaking preformulation studies.
Systematic preformulation studies on the active pharmaceutical ingredient (API) and on pilot formulations attempt to predict the viability of various formulations and methods of manufacture.
So what exactly are preformulation studies?
Preformulation studies include studies of:
- The physicochemical properties of manufactured batches of the API, and an assessment of their relevance to the final formulation
- The chemical and physical stability of the API
- The impurity profiles of the API, including the typical content of synthetic by-products and degradation products
- Chemical compatibility of the active with potential excipients
These studies give clues as to how to achieve the desired performance of the finished product.
Even after developing a formulation and method of manufacture on these principles, it is still necessary to confirm stability and bioavailability, but there is a smaller probability that the formulation will fail. If two or three formulations are developed in parallel, there is an even greater probability that one will be successful. Whilst there are costs associated with preformulation studies, they significantly minimize the risks of failure and increase the likelihood of producing a high quality product.
Outcomes to be expected from preformulation studies
The expected outcomes are that the product:
• Will deliver the drug to the site of action at the intended concentration.
• Will meet product specifications, including limits for content of drug and impurities, and suitable physicochemical tests such as dissolution rate, particle size of suspensions etc.
• Will be consistent from one dosage unit to another (eg tablet to tablet), from batch to batch, and from one manufacturing site to another. That includes consistent bioavailability.
• Will be chemically and physically stable for a suitable time period under convenient storage conditions. That is it continues to meet specifications.
• Can be manufactured at a cost that is consistent with the price that will be paid.
• As far as is possible, will be acceptable to the patient in terms of convenience and palatability.
Some specific benefits of conducting preformulation studies
Setting specifications for the API
With relevant in vitro information to hand, a manufacturer is in a better position to establish appropriate specifications for batches of the API so as to ensure an optimum and consistent performance for successive batches of the finished product.
Minimising development costs
By optimising the formulation before commencing costly bioavailability and bioequivalence studies, fewer such studies need be conducted.
Avoiding failures during long-term stability
Failure after say 2 or 3 years of long-term stability testing can set back a registration program significantly. Sound predictions as to the chemical and physicochemical stability of the active, and compatibility with excipients, other actives and the container, can minimize such failures.
Minimizing the need for in vivo bioavailability/bioequivalence studies
FDA s groundbreaking - development of the Biopharmaceutical Classification System 23 has narrowed the range of products for which bioavailability/bioequivalence studies must be conducted. In particular, BCS class 1 drugs can now avoid (or obtain a waiver of) in vivo (bioequivalence) studies. In Australia (and probably in other countries too), a drug s BCS classification is taken into account when deciding whether or not a bioequivalence study is needed for a new product or a change to an existing product24.
Biopharmaceutical classification involves determining:
1 The solubility of the active itself in aqueous media of various pH, and
2 The ability of the active to cross the gut wall (gastrointestinal permeability).
The more recent advent of biorelevant dissolution media in an attempt to better predict in vivo dissolution rate has the potential to extend this waiver to BCS class 2 drugs. Dressman et al25,26developed a series of these media, with some success in predicting the in vivo behaviour of different formulations of BCS Class II drugs, and alteration of their bioavailability in the presence of food. With more development, these studies may provide a means of optimizing formulations of BCS Class 2 drugs without the need for bioavailability or bioequivalence studies. As defined by Dressman et al, biorelevant dissolution media are of biological tonicity, pH and content of lecithin (mimicking bile salts). They attempt to reproduce conditions in the human stomach or proximal intestine.
In addition, development of suitable assay procedures is critical at this stage, both to ensure that the results of assay, stability and bioavailability and bioequivalence testing are sound, and so as to ensure that results are credible at the later (and critically important) regulatory stage. For the purposes of quality control and stability testing, assays must be established for each active in the presence of the others, thus requiring additional validation for specificity. Validated and specific methodology is needed for assays of drugs in a biological fluid, usually plasma. The presence of more than one drug complicates assays, especially for bioavailability studies when multiple metabolites and sometimes degradation products are also present.
Preliminary stability studies involve chemical, physicochemical and, when necessary, microbiological tests.
Stability studies are sometimes thought of as concerning only chemical stability but the stability of physicochemical and microbiological characteristics are also important. These are some examples of non-chemical characteristics that can change on aging:
- Particle size of suspensions (often 'disproportionation', that is big particles get bigger and small particles get smaller)
- Polymorphic form of the active when the active is present in solid form, eg in tablets, capsules, and suspensions
- Dissolution rate of solid dosage forms
- Preservative efficacy of multidose suspensions, both sterile and non-sterile
Failure to control the first three of these may compromise the rate and extent of absorption of the active.
It probably goes without saying that in general stability is reduced at higher temperature. For some drugs, stability is also reduced at high humidity.
An issue that occasionally rears it head is the acceptability of various excipients in different regulatory jurisdictions. WHO s Manual for a Drug Regulatory Authority discusses internationally available lists of acceptable excipients for different routes of administration27. Many authorities are vague on this point, and it is probably less of an issue in countries that do not have a strong DRA.