From the Discovery Lab to the Clinic and Pharmacy

The process of drug development can span the course of more than a decade, and costs an average of US$ 802 million (DiMasi et al, 2003). With limited funding for biotech and pharma during uncertain economic market conditions, companies need to be increasingly resourceful to succeed in their goal of developing a marketable drug.

One common way to conserve capital investments is by outsourcing of specialized research and development projects to established and experienced providers instead of building the technical capability internally in the short-term. Some companies, know as ‘virtual’ biotechs, outsource all of their development activities.

The use of highly specialized equipment and expertise at each stage of development varies greatly, and few biotechs, or even well established pharmaceutical companies can afford to develop a drug entirely from start to finish relying on in-house resources alone. Contract research providers such as BRI were created with a mandate to support biotechs and pharmaceutical companies in the development of their products, providing specialized technology and experience to accelerate the development cycle.

Modern drug development starts in the discovery laboratory. Today’s synthetically derived drugs are often molecules that are designed to act upon a known therapeutic target. For example, a small protein molecule may be modeled and custom synthesized to block a known biochemical pathway in the body. In-vitro and / or animal models may be established to demonstrate its efficacy. The molecule must then also satisfy initial screening of desirable drug properties such as absorption, distribution, metabolism, and elimination and toxicology. If the molecule is found to possess these desirable characteristics at this stage, it will be advanced from discovery onto the next stage of preclinical development.

Preclinical drug development goes beyond the discovery laboratory and this stage of development involves a comprehensive number of safety and toxicology studies aiming at demonstrating safety of the drug in an appropriate animal model, utilizing multiple species prior to testing in humans.

Another source of drug candidates receiving increasing interest is botanical medicines that have been used historically in their native region. While botanical preparations are commonly complex mixtures of extracted components of plant origin, contrary to a highly purified synthetic drug, botanical products must also undergo safety and toxicology assessment prior to being approved for market. In recent years, Health Canada has published new guidelines for the manufacturing and marketing of Natural Health Products (NHPs) which closely follow the GMP requirements for drug products.

Throughout the preclinical testing process, several other factors should be considered. The test article, regardless of source, must be fully chemically characterized, including molecular weight and structure, solubility, and hygroscopicity. Based on the characteristics of the compound, several final product formulations may be tested, looking for variations in the bioavailability between an oral liquid, tablet, or capsule or IV dose formulation. These formulations may be tested in animal models, and the most successful then manufactured in a pilot clinical batch. Another factor to consider in dose formulation is the dose concentration level. Multiple dose levels can be given in a dose escalation study to determine the Maximum Tolerated Dose (MTD).

Once these factors have been thoroughly investigated and a decision has been made determining the most favorable dose formulation and concentration, the first pilot batch for clinical studies can be manufactured. Finding the right CMO with experience in the specific formulation type is essential to proceeding smoothly through the difficult pilot manufacturing process. The CMO will carry out a series of QC tests on the finished product before their QC department releases it. These documents (called Batch Records) are used in the CMC submission for approval of the finished drug product.

In addition to QC release testing, a drug product should also go through stability testing, following ICH guidelines. In stability testing, products are subjected to two levels of controlled environment. The long-term conditions are set at 25°C and 60% Relative Humidity, considered to be average ambient conditions in North America. Materials are kept at these conditions for up to four years, and at regular time points samples are withdrawn for analysis of any degradation or breakdown of the active ingredient. If there are any degradation products, they must be identified and shown to also be safe. Significant loss of the active ingredient may indicate that an alternate formulation is required to maintain levels of the active ingredient within the label claim. In order to have more definitive results in a lesser time period, ICH outlines requirements for accelerated testing. The same materials placed in the long-term conditions are also placed at 40°C and 75% RH, to increase the rate of any degradation that may occur. Samples from the accelerated conditions are also tested at regular intervals and compared to previous time points, as well as to the materials at the long-term conditions. Excessive degradation early on at the accelerated conditions is a good indicator of degradation to come at the long-term conditions.

After data is collected on all the various aspects of preclinical testing, it is gathered and submitted to the appropriate regulatory agency in what is called the IND, or Investigational New Drug filing. Pre-IND meetings can be established with the FDA to discuss any potential weak areas in the data, in order to assist in filing a successful IND. Upon approval of the IND, clinical trials can begin.

Clinical trials involve four phases of testing. Each phase investigates a different aspect of the drug’s performance. Phase I trials are typically small trials designed to test the safety of the drug product in healthy volunteers. This may include a dose-range finding study to determine what amount of the drug is safe. Earlier preclinical testing would have established reasonable limits that are now confirmed in humans. Phase II trials combine further safety investigation along with efficacy. The drug product may now be given to subjects with the condition the drug has been shown to treat. Data collected at the clinic site includes information on the basic condition of each subject such as blood pressure and pulse rate and specific information on symptoms related to their condition such as pain, mobility, etc. Blood samples are also taken for analysis of blood chemistry, and pharmacokinetic (PK) samples are taken regularly to investigate the distribution of the drug in blood over time. Phase III studies build on successful Phase I and II studies, broadening the scale of investigation to multiple clinical sites and often involving thousands of subjects. Upon completion of Phase III trials, a marketing application or NDA is filed with the FDA. If approved, the drug product may now be marketed under the conditions in which it was tested. If a manufacturer would like to investigate further uses of the drug, or investigate post-market adverse events, a Phase IV trial is conducted to collect further data.

The drug development process can take over a decade to complete, and each stage of development requires a different type of expertise to see the product move forward. With the majority of drug candidates never making it to the pharmacy, it takes an experienced team of scientists to navigate the obstacles of development to a successful drug.

Glossary

ADME
Adsorption, Distribution, Metabolism and Excretion

API
Active Pharmaceutical Ingredient

Analytical Investigator
Person responsible for the analytical portion of a preclinical study

Batch Record
Documents the production of a drug substance or drug product under GMP including raw materials and equipment used in production

Calibration Curve
A plot of the analytical signal as a function of analyte concentration using standards of known concentration.

Certificate of Analysis
Document certifying the purity of a chemical or drug substance, including results summary of any tests carried out on the material related to purity.

CFR 21 Part 11
Section of the FDA guidance documents related to the handling and storage of electronic data and the use of electronic signatures

Chromatogram
A visual representation of the pattern of separated substances obtained by chromatography

Chromatography
Any of various techniques for the separation of complex mixtures that rely on the differential affinities of substances for a gas or liquid mobile medium and for a stationary adsorbing medium through which they pass, such as paper, gelatin, or magnesia

CMC
Chemistry Manufacturing and Controls

CMO
Contract Manufacturing Organization

CRO
Contract Research Organization

Dose Vehicle
The material in which a drug substance is solubilized in order to be evenly distributed when administered in preclinical studies.

Drug Product
The final formulation in which a drug is to be administered.

Drug Substance
A final concentration of active ingredient, which has not yet undergone formulation into a drug product.

Excipient
An inert material used in drug formulation to add desired properties such as volume, flowability, or to reduce stickiness.

FDA
Food and Drug Administration – regulates all aspects of drug production and sale for the United States.

Formulation
The process of developing a drug substance into a drug product, usually in the form of a tablet, capsule, or parenteral.

GC/MS
Gas Chromatography / Mass Spectrometry

GCP
Good Clinical Practices

GLP
Good Laboratory Practices

GMP
Good Manufacturing Practices

Health Canada
The Canadian agency regulating and reviewing pharmaceutical products in the Canadian marketing.

HPLC
High Performance Liquid Chromatography

ICH
International Conference of Harmonization

IND
Investigational New Drug

Internal Standard
A known concentration of a compound used during sample analysis to standardize results of the analyte, especially when run over multiple batches.

In Vitro
The study of a compound in an artificial environment (outside of a living organism).

In Vivo
The study of a compound within a living organism.

LC/MS
Liquid Chromatography / Mass Spectrometry

LC/MS/MS
Liquid Chromatography / Tandem Mass Spectrometry

LOD
Loss on Drying

LOQ
Limit of Quantitation

Method Validation
The process of ensuring the validity of an analytical method, including system suitability, selectivity, specificity, quantitation range, calibration linearity, assay accuracy, precision & recovery.

Mobile Phase
The solvent that is continuously applied to the column in LC applications, acting as a carrier for the sample solution.

MTD
Maximum Tolerated Dose

NCE
New Chemical Entity

NHP
Natural Health Product

NHPD
Natural Health Product Directorate

OOS
Out of Specification

OOT
Out of Tolerance

OTC
Over the Counter

Pharmacokinetics
The processes of absorption, distribution, metabolism, excretion and toxicology of drugs in the body. Most often quantified by the concentration of drug in plasma over time.

Placebo
An inactive substance or preparation used as a control in study to determine the effectiveness of a drug.

Plasma
A component of whole blood consisting mostly of water, blood proteins and inorganic electrolytes.

Quality Assurance
Systematic monitoring and evaluation of the various aspects of all relevant regulatory requirements to ensure that standards of quality are being met.

Quality Control
Ensuring the maintenance of proper standards in manufactured goods, especially by periodic random inspection of the product.

SOP
Standard Operating Procedure

USP
United States Pharmacopeia

LC/MS/MS Method Development Training

To integrate the mandate of BRI as a contract research company providing research infrastructure to pharmaceutical and biotech companies, BRI offer an in-house LC/MS/MS method development hands-on training program.

Novice mass spectrometry method development scientists are encouraged to take their method development project to BRI and operate on one of BRI’s LC/MS or LC/MS/MS instruments with coaching and discussion support from one of our experienced method development scientist on a one-on-one basis.

Based on our experience and feedback from our previous sponsors, this program has given emerging or rapid-growth biotech companies the ability to access BRI’s analytical and bioanalytical experience and develop core competency in the area of mass spectrometry and method development, while making advancement in the project at hand.

Rates are negotiable on a daily or weekly basis as the normal time frame for completion of a method development project.

For further details and inquires, please feel free to contact Ms. Clara Faan, VP Business Development (cfaan@bripharm.com).