REPRODUCIBLE MANUFACTURE

15 May

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.

Product Considerations

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.

INTELLECTUAL PROPERTY

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.

CONSUMER  ACCEPTABILITY

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.

CLAIMS SUPPORT

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  Materials

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”).

Monograph

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.

Product Performance

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).

SUMMARY

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.

ACKNOWLEDGMENTS

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.

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