gmp manufacturing for worldwide clinical trials

InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations

GMP MANUFACTURING FOR WORLDWIDE CLINICAL TRIALS

Richard Soltero, Ph.D.

Founder

InstantGMP

InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations2

Discussions

Flow of GMP Manufacturing processes Approaches to GMP compliance

throughout the world Impact on clinical trial supplies


ICH Q7A Good Manufacturing Practice

International Conference on Harmonization

ICH Member Countries –European Union (EU) - 27 countriesJapanUnited StatesAustraliaCanadaNorway


Basic of GMPs according to ICH Instructions and procedures are clear and

unambiguous Manufacturing processes are clearly defined and

controlled Facilities designed to minimize cross-

contamination and mix-ups Operators are trained Records demonstrate that all required steps

were taken Distribution minimizes any risk


Different approaches to GMPs compliance depending on country

There is a global disequilibrium – quality and compliance are different

A nation’s relative development dictates the level of compliance they can afford

ICH signatories have the best quality BRIC nations generally are struggling with

the cost of compliance, even while they recognize the value for international commerce


GMP starts with the Quality System Structure

First step of compliance is the quality system structure

Next is facility design that prevents cross contamination and mix-ups

Then control of materials

Finally documentation of manufacturing information


Manufacturing Facility

Facility and flow designed to minimize potential contamination and mix-ups

Defined areas for:Receipt

Quarantine

Storage

Production

Packaging

Washing


Small ScaleCTM Manufacturing Facility

Material flow


GMP Facility Inspections

FDA conducts facility inspections for products to be sold in the USDoesn’t include CTM facilities

Doesn’t include clinical stage products

UK and EU use UK’s “Orange Guide” to check compliance

China, Japan, India et al rely on local inspectors


Typical GMP Facilities in US and UK


GMP in India

Pharma companies in India don’t pay taxes for their first ten years

They don’t go through complex certification procedures

Over 20,000 pharma companies in India

Only 100 have been FDA inspected


GMP Facilities in India

Schedule M regulations were harmful to the small players in the pharmaceutical industry


GMP Facilities in India

So the government is cutting them some

slack


MaterialsOnly QA approved materials can be used in CTM manufacturing

Excipients Containers/Closures

ComponentsWork in Process


Getting ready for manufacturing – Control of Materials

No

Vendor Qualification

API , excipients and components

identified

YesPM InitiatesProject

VendorsQualified?

ProjectDefinitionCompleted

QualityManager

ProjectManager

SpecsApproved?

Assign Part #s,tests, methods,

Specs

Select Personnel and Roles

Yes

QualityManager


GMP in Russia 90% of materials used in Russia are from unknown

origins Only one out of every five drugs purchased in

Russia is produced domestically 19 of the top 20 producers of drugs sold in Russia

are foreign owned Only 50 of Russia’s 528 drug factories meet

international GMP standards Before 1991 the state was the only supplier,

customer and authority to create standards Compliance to plan was more important than

compliance with GMP standards


GMP in Russia In 2004 the EU GMP Guideline was approved as

Russian national standard GOST R 52249-2004 National standards are not mandatory

documents according to Russian Law There are multiple challenges to meeting GMP

in Russia including bureaucracy and corruption Pharma 2020 is the government's intended fix

$6 billion in industry-wide investment in training and infrastructure development, GMP practice development and R&D

In the meantime, producing or distributing CTM through CMOs in Russia carries some risk


Vendors

QA shall qualify vendors for materials used in CTM

Phase 1 CTMPaper based quality survey

Phase 2 CTMEither a paper based quality survey or an on-site audit

Phase 3 CTMOn-site audit


SpecificationsQA shall approve specifications of materials and components Test - A measurement of a quality attribute such as

potency or water content

Method - The procedure by which the quality attribute is measured

Limit - The acceptable range for the attribute

Other Requirements

Sampling Instructions

Safety and Handling


Specifications have version control to keep track of changes

Most recent specs apply, but old specs must be kept available for review

Specifications


Specifications can have Safety, Handling and Sampling instructions

Specifications


Specifications include Test, Methods and Limits that will go on Certificate of Analysis

Specifications


GMP in Japan Japan has meticulous, detailed and strategic local GMP

rules You may not know if a Japanese supplier or distributer is

in compliance; you just have to trust them Most GMP texts are in Japanese, rare to see local

pharmaceutical guidelines in English Japan is a signatory of ICH, but there are differences

between Japan’s and International GMP Japan applies a more thorough interpretation of GMPs

than ICH requires The Local Government and Certification Bodies

administer GMP in Japan


Process Flow – Material Management

Receipt at Warehouse Record into

I nventoryReleased

Quarantine,Test &

Release

No

Available for Bill of Materials &

ProductionYes

QualityManagerFacility

Manager


Receiving


Quality Testing and Release


Regulations issued in the 1980’s and 1990’s were supposed to strengthen China’s pharmaceutical manufacturing

GMP 2010 has become law Nearly 4,000 pharmaceutical companies

in China are small to medium size who will need significant capital to meet new standards

GMP in China


Nearly impossible to verify if Chinese produced product is in compliance

GMP guidelines in Chinese Locally inspected One standard for export and another for

local

GMP in China


GMP in China

Only a small % of Chinese factories have FDA inspections


GMP in China

The rest are inspected locally where corruption remains a possibility


Process Flow - Production

Master Production

Bill ofMaterials

ManufacturingI nstructions

Batch Production

ApproveBatch Record

QualityManager

FacilityManager

I n ProcessTests

Equipment

Sponsor


Master Production Record


Master Production Record - BOM


Master Production Record –Manufacturing Instructions


Batch Production Record –Manufacturing Instructions


Testing and Release

Samples pulled from production batch QC will test according to methods in

specifications In US, QA will disposition batch after

final product in made in the US in the UK and Europe, QP (Qualified

Person) is used for batch release


GMP in the UK GMP in the UK is based on is the 1968 Medicines Act “Guide to Good Pharmaceutical Manufacturing

Practice” issued in 1971 Basis for US GMP regulations Now known as the “Orange Guide” Essential reference for all pharmaceutical

manufacturing and distributing in the European continent.

GMP Inspectorate uses this document as their reference for checking the compliance of companies to EU GMP/GDP standards.


GMP in Brazil In the 70s and 80s, steep price control, high

inflation, weak intellectual property rights and absence of quality assurance affected drugs

ANIVSA (National Health Surveillance Agency like our FDA) started regulating generics in the 90s

ANIVSA revised its GMP in 2000s to be in line with WHO GMP standards

Now RDC 25 requires quality control and compliance of pharmaceuticals made or imported into Brazil


GMP in Brazil Despite the benefits of RDC 25 some manufacturers

opposed it due to the cost of compliance RDC eventually was narrowed down and bases the

certification or approval to “risks” of the product Risk levels 1 and 2 are considered low level while levels

3 and 4 are high The determination of the product risks will be made by

ANIVSA Only high risks pharmaceutical products require

certifications Level 1 and 2 products are not subjected for registration

procedures


Inventory


Tracking of CTM Distribution


GMP in Taiwan Regulated by Taiwan’s DOH (Department of Health) 1988, DOH’s required manufacturing plant to provide

PMFs (Plant Master File) as mandated by the international GMP

1998, Taiwan applied for PIC/S Pharmaceutical Inspection Co-Operation Scheme membership

In 2001, it expanded and updated its guidelines to include product distribution and recall, plant inspection, auditing and complaints.

Focused on export and international acceptance


GMP Inspections World Wide

PIC/S (Pharmaceutical Inspection Cooperation Scheme)

PIC/S references “Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients” (ICH Q7A)

Participants include Australia, Canada, Eastern Europe, EU, Malaysia, SA, Singapore, UK, US, Taiwan

Not participating: Brazil, Russia, India, China

InstantGMP: Electronic Manufacturing System for Small Pharmaceutical Operations

Messages No one GMP compliance system exists even

in countries that are signatories to ICH BRIC countries want to become compliant, but

they have a long way to go Most countries outside of Europe, Japan and

US have little control over quality or compliance

If you are manufacturing, packaging or distributing CTM world wide, you have to understand both local regulations and how they are (or are not) enforced

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