Investigational Product (Pharmaceutical) Management

Sudhakar Bangera MD, MMedSc Program Director, CDSA

Investigational Product

•  Definition (CDSCO GCP) -  A pharmaceutical product (including the

Comparator Product) being tested or used as reference in a clinical study

-  An Investigational Product may be an active chemical entity or a formulated dosage form

Investigational Product

•  Definition (ICH E6) -  Is a pharmaceutical form: •  of an active ingredient or placebo being tested or

used as a reference in a clinical trial •  including a product with a marketing authorization

when used or assembled (formulated or packaged) in a way different from the approved form or when used for unapproved indication, or

•  when used to gain further information about an approved use

Investigator Brochure

•  Chemical, pharmaceutical, toxicological, pharmacological and clinical data including the available data from previous and ongoing clinical studies

General Considerations

•  Physical, chemical, pharmaceutical properties and the formulation of the IP must be documented to permit appropriate safety measures to be taken during the course of a study

•  Instructions for the storage and handling of the dosage form should be documented

•  Any structural similarity(ies) to the other known compounds should be mentioned

Relevant Components of Protocol

•  Name and description of the investigational product(s)

•  Description of and justification for the route of administration, dosage regimen and treatment periods for IP and Comparator.

•  Accountability procedures for the investigational products including the comparator product

•  Subject withdrawal criteria (i.e. terminating IP)

Handling of the Product

•  Measures to be implemented to ensure the safe handling and storage of the pharmaceutical products.

•  Label should necessarily contain the following information: the words - “For Clinical Studies only”, the name or a code number of the study, name and contact numbers of the investigator, name of the institution, subject’s identification code

Data Handling and Management

•  Procedures for handling and processing records of effects and adverse events to the product(s) under study

Sponsor Responsibilities

•  Responsible for supplying the Investigational Product’s, including Comparator(s) and Placebo, if applicable

•  Products should be manufactured in accordance with the principles of GMP

•  Should be suitably packaged in the manner that will protect the product from deterioration and safeguard blinding procedures

•  Should be affixed with appropriate investigational labeling

Label and Labeling

•  “Label" is the written information on the drug/device itself or its packaging

•  “Labeling" refers to this label and any descriptive or informational literature accompanying the drug/ device

Label – Format

•  Name of the medicinal product •  Randomisation/ coding number •  Quantitative declaration of the active substance •  Excipients, preservatives •  Method of administration •  Warnings •  Shelf-life •  Storage precautions & conditions

Label – Format

•  Special precautions •  Instruction •  ‘For Clinical Research Use Only’ •  Batch number •  Name & Address of the Manufacturer

Labeling

•  Font size not less than 7pts and minimum of 3mm between lines

•  Legible •  Multi colored for clear distinguishing from

background •  Printed in English and perhaps local language •  No long sentences •  If the IP is packed in a vial, the label should not be

more than 3/4th of the bottle •  Generic name bolder than trade name •  Diagrams can be used to reduce the need of the text

Packaging

•  cGMP requirements for the control of drug product containers and closures 1.  Drug product containers and closures shall not be

reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements

2.  Container closure systems shall provide adequate protection against foreseeable external factors in storage and use that can cause deterioration or contamination of the drug product even while in transit

Packaging

3.  Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to ensure that they are suitable for their intended use

4.  Documentation of test methods, methods of cleaning, sterilizing, and processing to be maintained

5.  No. of units

Sponsor Responsibilities

•  Should not supply an Investigator/ Institution with the Product until the Sponsor obtains all required documentation (e.g. approval/ favorable opinion from EC and Regulatory Authorities

•  Document procedures and lay down responsibilities for: a)  Adequate and safe receipt, handling, storage,

reconstitution procedures and devices for product infusions, and dispensing of the Product

b)  Retrieval of unused Product from the Subjects and c)  Return of unused Product to the Sponsor (or its

alternative disposal procedure)

Sponsor Responsibilities

•  Maintain records for retrieval of IP (e.g. retrieval after study completion, expired product retrieval etc.)

•  Maintain records of the quantities of IP with proper batch numbers

•  Ensure that the Investigator is able to establish a system within his/ her Institution for proper management of IP as per the procedures

•  Should maintain sufficient samples from each batch and keep the record of their analyses and characteristics for reference

Sponsor Responsibilities

•  The coding system for the IP should include a mechanism that permits rapid identification of the products in case of a medical emergency

•  Patient Drug Accountability Record – 2 years after marketing application is approved or discontinued

Shipping

•  Tamper evident drug shipping bags

•  Cold chain •  Training for ‘Biopharmaceutical Shipping’

Monitor Responsibilities

•  The Monitor should verify (and wherever necessary make provisions to ensure) that a)  The IP is sufficiently available throughout the study

and is stored properly b)  Supplied only to subjects who are eligible to receive

it and at the specified dose(s) and time(s) c)  Subjects are provided with the necessary

instructions on proper handling of the product(s) d)  Prescribed procedures for storage, handling,

dispensing and return of IP are being followed and their compliance is being documented in a form as in the SOPs

Investigator Responsibilities

•  Investigator has the primary responsibility for investigational product(s) accountability at the study site(s)

•  Preferably the pharmacy department of the site should assume responsibility

•  Responsibility to be mentioned upfront in the study agreement

•  Maintain records of the product’s delivery to the study site, the inventory at the site, the use by each subject, and the return to the sponsor or the alternative disposal of the unused product(s). These records should include dates, quantities, batch/ serial numbers, expiry dates if applicable, and the unique code number assigned to the IP packs and study subjects

Investigator Responsibilities

•  Maintain records that describe that the subjects were provided the dosage specified by the protocol and reconcile all IP received from the sponsor.

•  Ensure that the product(s) are stored under specified conditions and are used only in accordance with the approved protocol

•  Should be thoroughly familiar with the safety, efficacy and appropriate use of the IP as described in the protocol, IB and other information sources provided by the sponsor from time to time

•  Ensure that all persons involved in the study are adequately informed about the IP

Pill Reminders

Mul$-­‐Alarm  Medica$on  Reminder  

Once-­‐A-­‐Day  Vibra$ng  Pendant  Reminder  

MeDose "Pediatric"

watch

Drug Disposal

•  Purpose-built, high temperature incineration with adequate flue gas cleaning – Best

•  Non-biodegradable antibiotics, antineoplastics and disinfectants should not be disposed of into the sewage system as they may kill bacteria necessary for the treatment of sewage, damage aquatic life or contaminate drinking water

•  Burning at low temperatures or in open containers results in release of toxic pollutants into the air

•  May allow drugs to be diverted for resale to the general public

•  Return to Sponsor or CTM company

Drug Disposal

•  Landfill: -  Place waste directly into a land disposal site without prior

treatment or preparation after immobilization by encapsulation or inertization

-  Open uncontrolled non-engineered dump •  Untreated wastes must be covered rapidly with large quantities

of municipal waste to prevent scavenging •  Can lead to pollution with the risk of drinking water

contamination

-  Engineered sanitary landfill •  Evacuated pit isolated from watercourses and above the water

table •  Each day’s solid waste is compacted and covered with soil to

maintain sanitary conditions

Drug Disposal

•  Waste immobilisation: Encapsulation -  Immobilizing the pharmaceuticals in a solid block within a

plastic or steel drum -  Clean drum is filled to 75% capacity with solid and semi-

solid pharmaceuticals, and the remaining space is filled by pouring in a mixture of lime, cement/ plastic foam/ bituminous sand and water in the proportions 15:15:5 (by weight) and the drum filled to capacity

-  Drum sealed by spot welding -  Placed at the base of a landfill and covered by municipal

solid waste

Drug Disposal

•  Waste immobilisation: Inertization -  Removing the packaging materials, paper, cardboard and

plastic from the pharmaceuticals. (Pills need to be removed from their blister packs)

-  The pharmaceuticals (65%) are then ground and a mix of lime (15%), cement (15%) and water (5%) added to form a homogenous paste

-  The paste is then transported in the liquid state by concrete mixer truck to a landfill and decanted into the normal urban waste. The paste then sets as a solid mass dispersed within the municipal solid waste

Drug Disposal

•  Sewer -  Syrups, antiseptics, and IV fluids, can be diluted with

water and flushed into the sewers in small quantities over a period of time into a fast flowing watercourses

•  Burning in open containers -  Very small quantities of waste pharmaceuticals -  Paper and cardboard packaging, if they are not to be

recycled, may be burnt. Polyvinyl chloride (PVC) plastic however must not be burnt

Drug Disposal

•  Medium temperature incineration -  Expired solid form pharmaceuticals mixed with solid

municipal waste (1:1000) -  A two–chamber incinerator that operates at the minimum

temperature of 850°C, with a combustion retention time of at least two seconds in the second chamber

•  *High temperature incineration using existing industrial plants (Cement kilns) -  > 1200°C -  For large quantities of solid and semi-solid

pharmaceuticals •  Chemical inactivation

Drug Disposal

•  SEM Disintegrators-DS 22 -  Waste is fed into the unit -  Falls into a destruction chamber -  5 rotating knives pass by 2

stationary bed knives -  Cut the waste smaller and smaller

with each pass -  Final waste is determined by an

interchangeable security screen -  Drops out of the destruction

chamber -  Evacuated to a waste collection

bin

Thank You