Supplier’s Approach t o TUPP Inf or m at ion...t o TUPP Inf or m at ion. 1. Concer ns and r egulat...

The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada.

Mike Polito04 March 2020

Technically Unavoidable Particle Profiles

Supplier’s Approach t o T UP P In f o r m a t io n

1 Co n c e r n s a n d r e g u la t o r y p r e s s u r e

2 Gu id e l in e s

3 Wh a t a r e T UP S ?

4 Ho w t o m a n a g e T UP s ?

5 Ho w t o c o m m u n ic a t e T UP P s ?

Agenda

Concerns and r e g u la t o r y p r e s s u r e

Foreign particles – Regulatory pressure increases

„Deviations were not

initiated for the

particles found in

retention samples for

Aluminum Hydroxide

batches“

(Form FDA 483, 9/2/10)

„…firm did not thoroughly

investigate particulate

contamination found in lot

(b)(4) of (b)(4) injection“

(Warning letter, 8/17/10)

„issuance of several

Form 483s to pharmaceutical

companies by FDA

investigators for

insufficient or incomplete

investigations of unusual

visible particles“(source: Technically Unavoidable Particle

Profile Guide, 2015, IPEC

4 Technically Unavoidable Particle Profiles

Foreign Particles – Threat for Drug Recalls

Voluntary recall issued for allergy nasal spray due to glass particles

Voluntary recall issued for Nexterone due to

particulate matter found

Voluntary recall issued for Levofloxacin due to presence of visible particulate matter

Voluntary recall issued for Vancomycin Hydrochloride due

to presence of particulate matter

Jan 2018

May 2018 Aug 2017

Jan 2018

Foreign particles – Regulatory pressure increases

FDA: “As an agency, we want to know that you understand what product you’remaking, so that you know what is or isn‘t acceptable… There are risk-based,science-based decisions that you need to make as the manufacturer of the final drugabout what you can tolerate in your incoming raw materials, including the excipients.So if you have particles, we would like to see that you understand what they are. Perhaps it‘s as simple having a discussion with your supplier and being able to explain to the agency what the particles are and why they are not a risk to public safety or patient safety, which is our prime concern. Risk management, good science, andalways keeping the safety of the patient in mind is what we‘re looking for.” Source: Atypical Visible Particles, industry roundtable, IPEC, Jul 2, 2012 – Pharmaceutical Technology, Volume 36, Issue 7, pp. 86-88


Safety implications for patients

Potential toxicity, immune response, infection…. (depending on route of administration, composition)

Chemical (toxic vs. inert), microbiological (e.g. viral RNA), physical concerns (sharp edges)

Violation of compendia & regulatory requirements

Disruption of supply chain and potential financial impacts thereof

Company reputation in case of market alerts or recalls

What are concerns on particles?


are typically considered as threat to final product

quality by customers of pharmaceutical industry

give rise to different measures of crisis-

management on side of customer such as

rejection of batches, stop of production and

blockage of final products

result in high efforts on customers and

manufacturers side, for example complaints,

(unnecessary) analysis and for-cause-audits

Customer Reaction – Typical Action CascadeFindings of foreign matter in products…


Guidelines

Associations defining the state of the art

Customer’s TUPP understanding

APIC and IPEC determine the current discussion

APIC

Currently the guidance from health authorities (EMA, FDA, others) or Pharmacopoeias (e.g. EP, USP) about particles in APIs is very limited

This lack of guidance has led to uncertainty of how to deal with insoluble matter, and has sometimes resulted in the unrealistic expectation that no single visible particle should be present in any amount of API, irrespective of its size or the overall amount present in a batch

Therefore the idea was born to develop such a guidance document as a basis for common understanding regarding the presence of particles in APIs


Benefit APIC Guide

Benefitsto the industry and to Health Authorities

Provides basis for a common understanding regarding presence of particles

1Shares possible investigation tools to support systematic and faster identification of root cause, appropriate corrective/preventive actions and risk assessments to enable the Quality Unit to make a solid GMP-oriented final product disposition decision.

2Provides current scientific, process, analytical, equipment and engineering knowledge and proven good practices to minimize presence and risk of foreign particles in APIs.

3 Provides proven test methods and scientifically based acceptance criteria for foreign particles in APIs.


Associations defining the state of the art

Customer’s TUPP understanding

APIC and IPEC determine the current discussion

IPEC

Observation of visible particlesnormally triggers investigation requiring extensive time, money and resources to be expended in identifying the source of the particles

The visible particles … pose minimal risk to patient safety

With current technologies, these particles are technically unavoidable and cannot be reduced to a lesser amount in the finished product

This guide encourages communication between excipient makers and users to reduce time, money and resources expended and to ensure adequate investigation

APIC

Currently the guidance from health authorities (EMA, FDA, others) or Pharmacopoeias (e.g. EP, USP) about particles in APIs is very limited

This lack of guidance has led to uncertainty of how to deal with insoluble matter, and has sometimes resulted in the unrealistic expectation that no single visible particle should be present in any amount of API, irrespective of its size or the overall amount present in a batch

Therefore the idea was born to develop such a guidance document as a basis for common understanding regarding the presence of particles in APIs


Benefits to the industry and to Health Authorities

BenefitIPEC Federation Guide

Provides a basis for a common understanding regarding the presence of visible particles

1A central cause of the increased concern is the issuance of several US FDA Form 483s to pharmaceutical companies by FDA investigators for insufficient or incomplete investigations of unusual, visible particles. These 483s did not prohibit these technically unavoidable particles, but addressed the insufficiency of the investigation process.

2IPEC’s TUPP guide provides a pathway to provide data on the identity and origin of these particles in excipients as a way of fulfilling the investigational component of the identification of unusual visible particles in excipients.

3The TUPP guide encourages communication between excipient producers and users to reduce time, money and resources expended and to ensure adequate investigation.


What are TUPS?

are visibly different from material when viewed with naked eye

can not be excluded for technical reasons

have been present for a long time in the history of the product

do not pose higher risk for patient safety for anyapplication of a particular lot, where they have beenfound

should not affect efficacy and quality of related drugproduct

are not homogeneously distributed over the batch size

number of these inherent, technically unavoidable particles is very small

IPEC Federation TUPP GuideTechnically unavoidable particles…


Types of technically unavoidable particles

Type of particles Origin Example

Charred particles, discolored Exposed to heat Discolored particles in Sucrose

Process materials of construction Wear of equipment Metal from piping, reactors etc.

Particles from routinely used gaskets, seals, filters etc. Wear of gaskets PTFE-particles, fibers from filters

Packaging component particles Wear of primary or secondary packaging materials

Cardboard, fibers from paper shedding, PP-suture material from big bags

Intrinsic components carried through from raw material (mined mat. or natural products) Raw material Discolored particles in sodium

chloride

Misshapen, morphological distinct particles Compression, agglomeration of material


HOW TO Manage T UP s ?

Presence of technically unavoidable, inherent particles in excipients is acknowledged by users,

but users request that suppliers…

support identification and characterization of the foreign particles

perform a root cause analysis on source of particles

master contamination (CAPA taken) to maintain the TUPs at an acceptable level

Reality and expectations

Technically Unavoidable Particle Profiles18

Testing of products according to internal monographs or against current Pharmacopeia is sometimes not sufficient to detect particles.

We routinely perform:

visual control of solids for particulate matter on lab samples of bulk material produced

appearance of solution test on labs samples (typically 10 g in 100 mL)

test for insoluble matter by filtration / weighing

All tests suffer from

low contamination level of foreign particles

inhomogeneity of distribution of foreign particles

QC control strategies

Technically Unavoidable Particle Profiles19

Limits on specification?

Specifications or limits for TUPs cannot be expected on CoAs: The insignificant number of particles

relative to batch size and the intermittent nature of their observance make a specification unrealistic

and unreliable

Information and QC-methods on “typical” amounts of TUPs may be item for discussion between user

and supplier

Excursions above these “typical” limits cannot always be prevented as the low levels and low

detectability may be beyond the capability of the process


Process of TUPP-preparation

Review of guidelines Evaluation of complaints Inspection of batches Analyse particles Preparation of risk-

assessment Collection of pictures

Review of manufacturing process

Identification of construction materials

Analysis of construction materials

Review CAPA situation

Ensure common understanding over process chain

Check for correctness Check for completeness Check for intellectual property Creation of customer-facing

reports

what is the situation ?

what is the reason ?

discussion and alignment

Planning Establishment RC-Analysis Finalization & Release Reporting


Trigger to initiate TUPP

1

32

Complaint trending

New Knowledge about manufacturing process

Trending in analytical testing


How to c o m m u n ic a t e T UP P S ?

Intention, quality policy towards foreign particles

Flow chart of manufacturing process

TUP information

Particle picture

Identity and composition

Origin

Mass balance

Root cause

Assessment of additional microbial and BSE risks

Mitigation actions

From Reactive to ProactiveDetailed information for each type of TUP


Picture and Identity


Chemical identity: Sodium hydroxide with traces of nickel and chromium

Root cause:

Sediment in the dropping device gets mobilized by turbulences due to pressure-fluctuations

Sediment-particles are included in the drops of sodium-hydroxide-melt and thus in the pellets

Information on identity, root cause and mass balance

Particle

weighIngredient

Concentration

in particle

Foreign

material per

particle

Technically

unavoidable

occurrence

Maximum

foreign

material per

100 kg

Maximum

concentration

per 100 kg

200 mg

nickel 100 ppm 20 µg

Typically

below

5 per 25 kg

400 µg 0,004 ppm

chromium 3 ppm 0,6 µg

Typically

below

5 per 25 kg

12 µg 0,00012 ppm

sodium

hydroxide

according to

CoA- - - -


Provision of guideline limits, material specifications and removal strategies


Information on microbial risks and mitigation


Concept behind TUPPValue added for Customer and Supplier

29

Establishes understanding of chemical manufacturing and its

limitations at customers side

Enables customers to perform a quick and reliable risk-

assessment for direct materials and final products

Helps to differentiate between complaints and typical

properties of a substance

Avoids unnecessary actions and crisis management

Finally will (might) reduce the number of complaints

Technically Unavoidable Particle Profiles

No excuse for lack of GMPs


It is not the intention of the information provided in TUPPs to

negotiate or to refuse any GMP obligation of the manufacturer of

pharmaceutical excipients and active pharmaceutical ingredients

Foreign contamination, not part of the TUPP, which can be a

failure of Good Manufacturing Practices (GMPs) is unacceptable

Thank you

Date post:	17-Jul-2020
Category:	Documents
Upload:	others
View:	2 times
Download:	0 times

Supplier’s Approach t o TUPP Inf or m at ion...t o TUPP Inf or m at ion. 1. Concer ns and r egulat...

Documents