Regulatory Landscape of Pharmaceutical Businesses

ABSTRACT 

Drug manufacturers (Biopharmaceutical and Pharmaceutical) companies undergoes a serious regulatory and inspections protocol because health and life are involved. The authorities validate that new products are carefully tested (both in pre-clinical and clinical stage) for consumption safety before marketing

INTRODUCTION

Regulatory Affairs is the proficiency and application of strategic enforcement of the legal frame work relating to biopharmaceutical, pharmaceuticals and related products. The modern drug regulations started in the 19^th century which systemized a solid foundation for the modern drug research, development and started to flourish.

WHY REGULATORY AFFAIRS

All substances are poison, the right prescription extricates a poison and a remedy. Drugs are not ordinary consumers product. Patients are not in position to decide on when to use drugs, which drugs to use and how to use them. Professionals should prescribe, however even the health professionals can’t act or prescribe drugs without proper guidelines & training (both theoretical and practical)

 REGULATORY AFFAIRS AIMS

• Ensures safety, efficacy and quality of medical products
• Ensures accuracy of product information
• Protects human health

ROLES OF REGULATORY BODIES

• Direct the manufacturers on regulatory conditions and climate that would influence their proposed actives
• Ensures obedience & compliance with all the applicable regulations and guidelines
• Provides regulatory intelligence in converting regulatory requirement into practical workable plans 

 DRUG DISCOVERY: Drug discovery simply means the researching and identification of a new medicinal product. Drugs can be discovered in so many ways such as Random screening, Molecular manipulation, molecular designing, drug metabolites, serendipity

 TARGET                                        PRIMARY                      PARALLEL             OPTIONAL POTENCY         EFFICACY

IDENTIFICATION                                     HTS                 MEDICAL CHEMISTRY     SELECTIVITY                    IN VIVO MODELS

                    THE DRUG DISCOVERY PROCESS IN THE 21TH CENTURY             

Screen development & HTS:  This is the method of finding a new medicinal product against a chosen target for a disease. High-Throughput Screening(HTS) is the discovery process widely used in Biopharmaceutical and Pharmaceutical industries

Heat to lead (lead generation): This is a phase in drug discovery where molecule(small) from HTS are classified and undergo limited optimization to identify lead optimization

Lead optimization: The goal of this phase is to transfer a suitable compound for testing in humans by subjecting a given lead to a development process to optimize its properties. A key step in lead optimization include increasing the pharmacological efficacy and mechanism of action on a medicinal product

Candidate selection: The is the process by which a drug candidate is designed after the initial compound has been identified

                                                        (Bleicher et al., 2003)

DRUG DEVELOPMENT

This is the process of formulating a new medicinal product once a lead compound has been identified through the process of drug discovery. Classification of drugs

• Active Pharmaceutical Ingredients (API)
• The excipients

Active pharmaceutical ingredients (API): This is the main drug in any medicinal product which influences the body when taken. e.g.  acetaminophen in a pain relief tablet

Excipients: This is simply a substance added to a medicinal product, so it is suitable to administer.

Types of excipients. Coating (e.g. shellac, zinc), preservatives (antioxidants like vitamin a, citric acid)

 GUIDELINES FOR DISCOVERY AND DEVELOPMENT

• ICHQ1A – STABILITY TESTING. This guideline provides a clear proof on how the quality of medicinal product varies under environmental influence such as humidity and temperature
• ICHQ1B – PHOTOSTABILITY TESTING. This guideline indicates that medicinal products must be photo tested to guarantee safety after the exposure to light
• ICHQ1C – This are newly produced drugs from a different manufacturer but contains the same active substances. This testing is done to certify a drug under different factors
• ICHQ1D – This is the testing of samples at different design factors (factors like container size, strength)
• ICHQ1E – This is the assessment of stability data which can be used to retest the shelf life of a medicinal product
• ICHQ1F – The guidelines describe the manufacturing process development and the risk of quality by design
• ICHQ10 – This guideline helps to match various quality system across the life cycle

REGULATIONS FOR DISCOVERY AND DEVELOPMENT

• Regulation (EC) No 1394/2007

STANDARDS FOR DISCOVERY AND DEVELOPMENT

• ISO 10006:2003
• ISO 11239:2012
• E 2500:13

PRE-CLINICAL TRIALS

This is a phase where important feasibility testing and drug safety data are collected. This involves all the necessary task to advance a new medicinal product through manufacturing, formulation, pharmacology, pharmacokinetics &toxicology testing. All this task must be accomplished in a healthy and regulatory compliant to ensure the quality of data and safety of clinical trials participant         (‘Pre-clinical development’, 2018)

BASIC GOALS

• Classify the pharmacological properties PD (mode of action)
• Establish a safe dose level for human exposure
• Finding the parameters for clinical monitoring of effect

 Pharmacology This is the mode of inspecting drugs and their effect on organisms(biological).  

Pharmacokinetics:The analytical movement of medicine within the body. The step involves                                                        

• Absorption
• Distribution
• Metabolism
• Excretion

Toxicology: This is the systematic research of toxic substance and its effect. Testing of toxicology includes

• Repeat dose testing
• Genotoxicity testing
• Carcinogenicity testing

CLINICAL TRIALS

This is the method of diagnosing & treating of health conditions. This stage of drug development comprises of four phases.

PHASE I: This is the first phase in clinical trial. At this stage, the researcher administers the new drug to a few healthy volunteers (70 people) to examine the potential toxicity. The phase main aims are to determine the highest dose patients can take without side effect. This trial takes about a year and the success will lead to phase to trial.

PHASE II: At this phase, the new drug will be administered to people living with the disease (about 300 carriers) to determine the effectiveness.

PHASE III: At this phase, the drug will be administered to huge population (about 2500 patients) with the disease in the same clinics or hospital. This phase confirms the effectiveness & side effect of the drug and will last for several years (about 3 years). It’s the longest trial phase in clinical trial

PHASE IV: This final phase determines the long-term effect of the new product i.e. whether a drug reduces agitation

CLINICAL TRIAL RISK ASSESSMENT: This is the fundamental role of the sponsor to ensure the rights and safety of subjects are protected. Risk (the medicine may not work thereby causing harm to volunteers)

GUIDELINES FOR PRE-CLINICAL AND CLINICAL TRIALS

• ICHM3: This guideline characterizes the principles for non-clinical safety evaluation
• ICHS1A-C: The guidelines are based on testing of rodent carcinogenicity for human pharmaceuticals
• ICHS3A: The guideline describes the exposure assessment in toxicity studies
• ICHS2: Gives a description of test battery for genotoxicity
• ICHS4: The guideline maps the minimum duration toxicology (rodent 6months, nonrodent 9months)
• ICHS8: The guideline evaluates nonclinical testing for immunoenhancement
• ICHE6A-B

REGULATIONS FOR PRE-CLINICAL AND CLINICAL TRIALS

• Regulation (EC) No 45/2001: The regulations determine the reaction of any medicinal products. It also analyzes the absorption-distribution of drugs
• Regulation (EU) No 536/2016:
• Regulation (EC) No 190/2006
• Regulation (EC) No 596/2009
• Regulation (EU) No 45/2001

STADARDS FOR PRE-CLINICAL AND CLINICALS

• ISO 1415:2011 – This standard gives details of clinical investigations in human subjects for safety evaluations
• ISO 15189 – The standards defines the requirements of quality management system in laboratory testing
• ISO 14155:2001 – Clinical analysis in human  
• ASTM E691 – The standard defines the method for analyzing and treating of results

 MARKET AUTHORIZATION (MA)

This is a compulsory license to place a new drug in the market to be used by patients. All biopharmaceutical and pharmaceutical companies require this license to market their product and can obtain the authorization once the application has been approved by the competent authorities. Before applying for the market authorization application, the compliance team must submit an important dossier called Common Technical Documents (CTD) to the authority for evaluation and approval. This document holds all the data and information’s obtained at the previous stages of drug development life cycle.

The Common Technical Document is made up of five fixed module contents

                                                     Module 1

                           Module 2

                                           Module 3                   Module 4                  Module 5

                                                                                 (Cowley and Camp, 2015)

Module 1: Documentation of files / information e.g. manufacturing license, labelling information

Module 2: Summarizes of the quality and clinical information’s which are shown here

Module 3: This document shows how the medicinal product are made (quality)

Module 4: Non-clinical study reports are displayed here (both in vivo & vitro)

Module 5: Details of efficacy and safety are shown here

 MARKET AUTHORIZATION PROCEDURES

                                                       (Marketingauthorisation, 2015)

Centralized Procedure:  This procedure involves all the EU members and takes about 210 days

Mutual Recognition procedure: This procedure involves one or more members in the EU zone and takes 90 days with 30days additional time for translation review purpose

Decentralization Procedure: This procedure includes one or more EU state and takes 210 days with 30 days review time

National Procedure: this procedure involves only one EU member state takes 210 days

                                                                                 (Marketing authorisation, 2015)

GOOD MANUFACTURING PRODUCT (GMP)

This are checks and measures that ensure medicinal products are produce and controlled in accordance to the quality standard. The goal of GMP is to minimize the risk in biopharmaceutical and pharmaceutical production that cannot be eliminated through testing the final product

  INITIAL MARKET AUTHORIZATION

                 First day                                                                                                   Day 210

                                                                           (Nieto-Gutierrez, 2010)

PHARMACOVIGILANCE

Pharmacovigilance is the act of supervising the effect of new medicinal product after they have been certified for patients use

    AIMS

• To enhance patient safety and care of people
• To publicize clinical training and health awareness to public and professional

POST MARKET SURVEILLANCE (PMS)

This is the method of acquiring information about a medicinal product after the market authorization.

Reason for post market surveillance

• To evaluate signs of risk related to drug use
• To diagnose and predict the unexpected risk

Source of post market information

• Customers scrutiny
• Consumers complaints
• Internet
• Post CE market clinical trial

GUIDELINES FOR MARKET AUTHORIZATION AND POST MARKET AUTHORIZATION

• ICHE2E: This is the guideline for planning pharmacovigilance activities
• ICHE2D: Procedure for post approval safety data management
• ICHM4: The guideline gives a format for Technical Document application
• ICHM4Q

REGULATIONS FOR MARKET AUTHORIZATION AND POST MARKET AUTHORIZATION

• Directive No 2001/20EC Regulation (EC) No 726/2004: Authorization and supervision of products for human and animal consumption 
• Regulation (EU) No 520/2012
• Regulation (EU) 712/2012
• Regulation (EC) No 1768/92

STANDARDS FOR MARKET AUTHORIZATION AND POST MARKET AUTHORIZATION

• ISO 9001:2015- The standard analyzes the system for quality management
• ISO 1522:1999 – The standards emphasis on documenting   procedures for life cycle model
• ISO 15394:2009 – This standard gives a clear detail on labelling and packaging of products (2D barcode)
• ISO 11239:2012
• BS EN ISO 15378:2007 –

RISK MANAGEMENT ACROSS THE LIFE CYCLE

                                             phase I – phase iii           phase iv

                                                                          Approval

RENEWALS

Medicinal products are always renewed after 5 years it was approved. Then application for renewal should always be placed 9 months before the product expires

Important documents for renewal

• Expert statement
• Declaration
• Variation
• GMP compliance certificate

VARATION

Means slightly change in medicinal product. Drug manufacturers are mandated to give details of any key adjustment on the product like company name, address etc.  Variation depends on the changes, not all changes will be acknowledged as variation procedure but extensive changes like change in excipients and active ingredients will be submitted as extension of market authorization

PATIENT INFORMATION LEAFLET

This is a booklet that accompanies a medicinal product. This book contains the vital information about a drug like dosage & directions, side effect, warning and precautions, manufacturers address and compositions.

COUNTERFEIT MEDICINES

This are fake drugs that are sold to patients as original that may be harmful for patient’s consumption. The drug may hold unlike ingredients, noxious ingredients, false address etc.

 Effect of counterfeit

• Health hazard
• Reputation deficit

GENERIC MEDICINES

This are similar drugs that are in existence but different manufacturer which encloses the same active ingredients

A generic medicine must

• Have alike prescription and serve the same purpose
• Alike API (active ingredients ingredient)
• Comply with GMP regulations

LABELLING AND PACKAGING

Labelling: This is an identifier (paper or polymer) attached to the body of a product which describes the product

Functions of labelling

• Gives details of a product like ingredients, manufacturing and expiring date
• Gives details of prescription & dosage
• Safety warnings and precautions

Types of label

• Manufacturer label
• Dispensing label

Manufacturer label: This is a label from the manufacturer which contains medicinal details, directives to be used by a professional.

Labels may contain

• Manufacturers name e.g. companies name and address
• Total sum e.g. 50 capsules
• Prescription e.g. 2 tablets daily
• Warnings e.g. avoid exposure to sunlight
• Price tags
• Date of manufacturing & expiring date
• Dose strength e.g. 250mg

Packaging: This is the means of protecting and promoting of a new product. It can also serve as an identifier to identify the content of a product.

Types of packaging

• Primary packaging
• Secondary packaging
• Tertiary packaging

Primary packaging: This is the type of packaging that grips the content of the product against contamination e.g. blisters, bottles

Secondary packaging: This is the second packaging material that protects the primary content e.g. small cartons

Tertiary packaging: This is used for bulky products which protects both the primary and secondary contents

Materials used in packaging

• Glass
• Plastic
• Rubbers
• papers

FALSIFIED MEDICINE  

Falsified medicine are harmful illegal medicinal products which are been sold as original in the market that maybe harmful to patients. This unauthorized product may contain wrong ingredient and normal ingredients but poor in quality and because they weren’t evaluated by a competent authority, they could be harmful for human consumption.

NEW FALSIFIED MEDICINE REGULATIONS (: REGULATION EU NO 2010/161, DIRECTIVE 2010/83/EC)

This regulation was published on February 9^th, 2016 which will be implemented on February 2109. The purpose of the regulation is to impede access to both fake and second-rated drugs for the interest of people, they are focused directly on improving the safety of the pharmacotherapy of patients.        (Delegated Regulation, 2016)

Tamper-evident seal: This method will be used after a new product has been developed to avert manipulation. The seal protects the drug against undesired opening and will not be issued out when tampered with

                Image of tamper evident seal                                 

                 (The Art of Tamper Evidence from Securikett, 2017)

Unique identifier: This is a verification device that determines the authenticity of a product & also differentiates it from another. The regulation requires that product must be coded with an identity number on its body, such number may include expiring date, product serial & batch number.      (Delegated Regulation, 2016) 

            Image of 2D barcode                                                                   Image of unique identifer scanner

 (Concern among pharmacists over Falsified Medicines Directive, 2017) ,      (LTD, 2018)                                                                          

 QUESTIONS 2

IMPORTANCE OF GUIDELINES

• Guidelines assures consumers safety and well-being unlike counterfeit drugs that did not comply with the guidelines
• Guidelines increases ethical awareness
• Economizes resources, development time and minimizes human exposure

IMPORTANCE OF STANDARDS

• Assist regulatory authorities & sponsors in compliance evaluation
• Certified product gives consumers safety confidence e.g. any product certified by SON (Standard Organization of Nigeria) are seen to be safe
• Products manufactured under ISO standards are highly recognized   in the international market.
• Certification body helps in market inspections
• Also helps in licensing a new product

IMPORTANCE OF REGULATIONS

• Helps manufacturers to improve on their output manufacturing process
• Helps to protect rights, safety and wellbeing of patients
• Monitor advertising and promotion of medicines
• Supplies information on products rational use  
• Regulation compliance helps during inspections

REFERENCE

1. Bleicher, K. et al. (2003) ‘Hit and lead generation: beyond high-throughput screening’, Nature Reviews. Drug Discovery, 2(5), pp. 369–78. doi: 10.1038/nrd1086.
2. Concern among pharmacists over Falsified Medicines Directive (2017). Available at: https://www.securingindustry.com/pharmaceuticals/concern-among-pharmacists-over-falsified-medicines-directive-/s40/a6402/ (Accessed: 22 November 2018).
3. Cowley, D. and Camp, B. (2015) ‘Clinical Development – Drugs’, p. 33.
4. Delegated Regulation (2016) OJ L. Available at: http://data.europa.eu/eli/reg_del/2016/161/oj/eng (Accessed: 21 November 2018).
5. LTD, B. T. (2018) What is the Falsified Medicines Directive (FMD) ? | News, Barcode Technologies LTD. Available at: https://www.barcode-uk.com/insight/what-is-the-falsified-medicines-directive-fmd-/News (Accessed: 22 November 2018).
6. Marketing authorisation (2015). Available at: https://www.printfriendly.com/p/g/U5KrG7 (Accessed: 22 November 2018).
7. Nieto-Gutierrez, M. (2010) ‘Non-clinical Assessment Requirements’, p. 37.
8. ‘Pre-clinical development’ (2018) Wikipedia. Available at: https://en.wikipedia.org/w/index.php?title=Pre-clinical_development&oldid=854599404 (Accessed: 30 October 2018).
9. The Art of Tamper Evidence from Securikett (2017) Authentication News. Available at: https://www.reconnaissance.net/authentication-news/issues/april-2017/ (Accessed: 22 November 2018).