Considerable effort is expended in ensuring that any formulation developed is safe, efficacious, and stable. As the product enters the marketplace, the formulation moves from the laboratory to larger production areas. The degree of control that the formulator can employ in the laboratory is significantly reduced, and con- siderations such as degree of mixing and heating and cooling rates become more significant.
Formulators should consider how the formulation will be manufactured at the time they produce their first laboratory sample, and recognize the difference between laboratory and scaled production in terms of raw materials and finished product.
Raw Material Considerations
A scale-up of formulation has two significant consequences for raw materials
B Health and safety risk of the material
B Handling of the material in bulk
In a laboratory setting, the risks posed by the majority of ingredients used in topical acne products are small and manageable. As scale-up occurs, the quantity of material increases and, as a result, the risk posed by materials that may be con- sidered essentially nonhazardous in a laboratory setting increases. Powders or sur- factants handled in larger quantities can pose a significantly higher risk. A risk assessment should always be undertaken and should take into account the quantity of material being handled, the environment in which it will be handled, and the extent to which negative effects could be ameliorated through training and the use of personal protective equipment.
Normal laboratory production usually entails handling of small quantities of raw materials in receptacles that allow easy removal. This may not be the case when the product is scaled up to full production size. Formulators should consider the way in which the material will be handled, the type of packaging in which it arrives, and whether any special handling equipment is required to enable it to be used safely and efficiently. Early discussion with appropriate personnel is essen- tial if difficulties are to be avoided.
Manufacture of bulk in a laboratory allows much greater intervention from the for- mulator than is possible in a production environment. The formulator should con- sider the method of manufacturing on a larger scale from first laboratory sample, through understanding the type of equipment that will ultimately be used. Pro- duction processes that are achievable in the laboratory are often not reproducible on a larger scale. These may include heating and cooling rates, and the type and amount of mixing experienced. Individual products will vary in the extent to which they are affected by these considerations, but as a general rule emulsions are likely to be the most susceptible.
The use of intermediate-sized mixing vessels in pilot facilities allows the for- mulator to assess the feasibility of manufacture and optimize the production method. Texture, efficacy, and stability are all attributes that may be affected during scale-up, and formulators should consider what testing needs to be carried out on pilot and full production batches before releasing the product for use by a wider population. As was seen earlier, there are clear requirements to test a range of pilot studies when considering stability and it is good practice, even when not legally required, to test batches produced in a production environ- ment. Robust pilot studies leading to a consistent, reproducible method of manufac- ture are essential for the long-term success of the formulation.
A patent is designed to protect the intellectual property of an individual or organ- ization, and can cover raw materials, product formulations, claims, and techniques. Patents may be filed in individual countries or as world patents, where a range of countries may be specified. Patents last up to 20 years, but the existence of pub- lished patent does not always mean that the patent is in force, as a fee must be paid each year to maintain continued validity.
Formulations should be screened by an appropriate expert in the field to identify potential patent infringements. This can save both considerable amount of time and money.
As has been stated earlier, consumer acceptability is critical to the long-term success of the product. Trials to gauge consumer opinion should be an integral part of a pro- ducts development. Products that use a prescribed drug can still be evaluated, but this will often be done on the base only during development and attributes confirmed during the follow-up clinical studies. Formulators should always confirm the regulatory requirements surrounding this type of trial before commen- cing any such trials.
Consumer trials may involve panels of volunteers trying products under controlled or uncontrolled conditions. This may take place in many locations such as shopping malls, public halls, and in consumers’ homes. All trials use typical consumers to try products either once or over an extended period of time and give their opinion either through interview or via a written questionnaire.
An alternative approach is the use of sensory panels. These are small groups of volunteers who have shown a level of ability to be able to detect differences between products in a particular grouping, for example, fragrance, color, or touch. They may have undergone additional training to enhance this skill or to be able to describe their experience using a consistent language approach. Sensory testing offers a way of making a reproducible assessment of different pro- ducts, often comparing test products to a known standard or control. The infor- mation provided allows the formulator to modify the in-use characteristics in critical areas. There are a number of ways in which such data can be presented; one such way is shown in Figure 6.
These types of tests can also be used to compare new formulations with current formulae, where changes need to be made, or with other products already marketed to assess their comparable attributes.
Sensory panels can be considered to offer a more consistent subjective assess- ment of product characteristics. The test will only be effective if the parameters chosen are those desired by the end consumer. When carrying out uncontrolled user trials, the wording of the questions should be neutral to avoid introducing bias, and so inducing the trial subjects to give the answer the formulator desires. Similar precautions should also be taken with controlled trials, where trial subjects are questioned as to their views. Inexperienced or biased trial supervisors risk
skewing the results in such a way that false positives are received that are not repeated when the general consumer uses the product.
Consultation with market research experts on conducting trials is important, as understanding the dynamics of such trials is key to meaningful results.
It is a requirement that any claims made in relation to products are truthful. Formulators need to be aware when commencing formulation of the claims to be made and should consider the ways in which these could be delivered.
Care must be exercised in this area regarding the nature of the claim being made for the product. Formulators need to be clear of the local regulatory require- ments surrounding the difference between claims that are purely cosmetic and those that may be considered to be medicinal.
Claims made for formulations fall into these broad categories:
B Claims made for specific or groups of raw materials.
B Claims made based on monograph requirements.
B Claims made based on the product function.
B Claims based on product performance.
Raw material claims are made based either on the inclusion of an ingredient (“con- tains Chamomile”), its reported action (“contains Chamomile renowned for its soothing properties”), or testing (“contains alpha bisabalol, the active agent of Chamomile, which has been shown to reduce irritation”).
There are certain claims that are justified by recognition of the inclusion in legis- lation. Primary among these are the acne claims made in the U.S. monograph following the inclusion of a prescribed level of salicylic acid, sulfur, or resorcinol, or combinations of the latter two (5).
Product Function Claims
Such claims justify the function of a particular product, for example, shampoo and moisturiser.
Certain claims may only be attributable to the whole product rather than individual ingredients. Such claims usually quantify the action of the product function, for example, product X decreases sebum by 30%.
CLAIMS SUPPORT TESTING
With the exception of claims made for product function or based on ingredients included in monograph, some form of claim substantiation should be carried out. These may be labeled as clinical or claims substantiation trials but it is best
practice to conduct any in vivo trial in accordance with Good Clinical Practice
(GCP) principles and any additional local regulatory requirement.
Careful thought should be given to the type and nature of the trial, and this should only be carried out if the benefits justify the potential risks. Any information on the trial product should support the proposed trial and be able to be used to produce a trial protocol. This protocol should be reviewed and approved by an appropriate body.
The safety of the trial subjects is of paramount importance at all times and any trial should always be the responsibility of a qualified physician. Screening of any potential trial subject should take into account their health and the impact the trial may have on them. Informed consent should be obtained from every subject prior to participation in any trial.
Each individual involved in conducting a trial should be qualified and trained appropriately. All trial information should be gathered and used in a way that allows accurate analysis and conclusions to be drawn. Records should always be stored in a secure and confidential way and comply with any local regulatory requirement.
Trial products should be made in accordance with appropriate good manufac- turing practice and used as stated in the approved protocol. There should be in place a method of auditing the trial to confirm that it was carried out according to the protocol.
ICH has produced guidelines on conducting clinical trials, and formulators will find important information that will allow them to perform high-quality studies (12). Although these guidelines are widely recognized, formulators should confirm before commencing clinical trials that local regulatory requirements have been satisfied.
For claims that are more cosmetic in nature, the European Cosmetic, Toile- tries, and Perfumery Association publish guidance on the evaluation of the efficacy of cosmetic products (13).
Topical anti-acne products covers a wide range of technology, regulatory, and product types. Good understanding of the fundamental formulation building blocks is essential in order to maximize the effectiveness of the range of ingredients available. A working knowledge of the activities that go to support the formulation enables the formulator to develop a clear strategy to deliver the desired stable, effi- cacious product with the minimum of problems.
This chapter has described many of the elements required to develop high- quality formulations that meet consumer ’s needs and expectations. The formulator is encouraged to use this only as a starting point and not to be afraid to carry out any experiment with the myriad of possible combinations of ingredients to delight new and existing users of topical acne products.
The author would like to thank all those who helped in the preparation of this manuscript, with special thanks to Patrick Love, Steve Barton, Nick Moody, and Diane Pavis.