Industry Perspective on Annex 1...Pharmaceutical Manufacturing & Quality: Emerging Regulations and Their Impact Industry Perspective on Annex 1 Tuesday, 22. September 2020 Gabriele

Pharmaceutical Manufacturing & Quality: Emerging

Regulations and Their Impact

Industry Perspective on Annex 1

Tuesday, 22. September 2020

Gabriele Gori PDA Co-Chair Annex 1

Di Morris PHSS Co-Chair Annex 1

DISCLAIMER: The views and opinions expressed in this presentation are those of the authors and do

not necessarily represent official policy or position of GlaxoSmithKline

2

History of Annex 1

COPYRIGHT © PDA 2018

3

Rationale


4

Regulatory Stakeholders


EU – 28 Member States

PICS – 54 Agencies

WHO – 194 members

Annex 1 Working Group – UK; Japan; Germany; Ireland; Poland; Switzerland; Australia; US; Singapore; Canada; Taiwan

5

Industry Stakeholders


6

Annex 1 Format


General OverviewSection Number

• Additional areas (other than sterile medicinal products) where the general principles of the annex can be applied1 Scope

• General Principles as applied to the manufacture of medicinal products. Includes requirements for Contamination Control Strategy2 Principles

• Highlights the specific requirements of the PQS when applied to sterile medicinal products3 Pharmaceutical Quality System (PQS)

• Guidance on the requirements for specific training knowledge and skills. Also gives guidance to the qualification of personnel4 Personnel

• General guidance regarding the specific needs for premises design and also guidance on the qualification of premises including the use of barrier technology5 Premises

• General guidance on the design and operation of equipment6 Equipment

• Guidance with regards to the special requirements of utilities such as water, air and vacuum7 Utilities

7

Annex 1 Format continued


General OverviewSection Number

• Discuss the approaches to be taken with regards to aseptic and terminal sterilization processes. Also discusses different technologies such as single use, lyophilization and BFS/FFS where specific requirements may be required. Discuss approaches to sterilization

8 Production and specific technologies

• This section differs from guidance given in Section 5 in that the guidance here applies to ongoing routine monitoring with regards to the setting of alert limits and reviewing trend data

• The section also gives guidance on the requirements of Aseptic Process Simulation

9 Viable and non viable environmental and process monitoring

• Give guidance on some of the specific Quality Control requirements relating to sterile medicinal products10 Quality Control

• Explanation of specific terminology11 Glossary

8

Revision process


AND THEN – SECOND TARGETED CONSULTATION

9

Targeted Consultation of Annex 1 Version 12 via 12 appointed commenting groups – the final stage of revision!


2020 Consultation with Targeted commenting groups following the public

stakeholder consultation in 2017.

Targeted Sections and clauses of Annex 1 v12 – encouragement not to repeat

comments from last public consultation (that received 6218 comments).

There are other significant comments both for the targeted clauses and over the

complete document.

EMA extended the commenting deadline to 20 July 2020 providing more time for

comment collation and review before submission.

The PDA have facilitated an ‘All commenting groups’ co-ordination series of Tcon

discussions to promote harmonisation and consensus. Each group individually

provided comments to the EC/ EMA but one combined covering letter was sent to

make clear industry expectations and concerns with version 12.

10

Associations’ Letter


1. The Annex should be flexible to support the use of appropriate alternative

approaches.

2. There must be clear interpretation of the Annex.

• Avoid use of specific examples

• Clear distinctions between similar but different technologies and approaches

3. More work is needed.

Associations have offered to help with training/education programmes, once the Annex

is approved.

11

PDA commenting process


• Core Team («Annex 1 Task Force», 2° wave): 12 experts from 10 companies from US, EU, ASIA, in

addition to consultants and PDA

• Solicited comments from 10K plus PDA members

• More than 25 meetings (teleconf), and hundreds of working hours

• Additional effort with BioPhorum (BPOG) to develop studies and generate&analize data on PUPSIT

• Overall, 88 Comments reviewed and endorsed by the PDA Science Advisory Boards (SAB) and then

by the Board

• Coordination of 9 Meetings (teleconf) with the representatives of the other 11 professional and trade

associations invited by EC to provide comments to the Annex (draft v12), with the purpose to verify

alignment and potential areas requiring further discussion

• Other professional and trade associations worked in the same way collating comments

12

Positives from current version


• Better structure of the annex

• More alignment to Contamination Control Strategy

• Increased principles of Quality Risk Management

• Clarity between ‘hard goods’ and ‘terminally sterilised products’ in that F0 not relevant for hard

goods

• For lyophilizers loaded by automated closed systems or located within systems that exclude

operator intervention, the frequency of sterilization should be justified and documented as part of

the CCS

• Changes in microbial flora type and numbers and predominance of specific organisms. Particular

attention should be given to objectionable organisms or those that can be difficult to control such

as spore-forming microorganisms.

13

Contamination Control Strategy (CCS)


Definition in Annex 1 Glossary*:

Contamination Control Strategy (CCS) – A planned set of controls for microorganisms, pyrogens

and particulates, derived from current product and process understanding that assures process

performance and product quality. The controls can include parameters and attributes related to

active substance, excipient and drug product materials and components, facility and equipment

operating conditions, in process controls, finished product specifications, and the associated

methods and frequency of monitoring and control.

*Also from EU GMP Annex 15 and derived from ICH Q10.

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production

Quality systems

deviation, investigation,

CAPA, change control,

complaints, continuous

improvement

equipment

design, qualification,

maintenance, calibration,

cleaning, sterilization

cleaning

validation

SHT,

CCIT,

facilities / utilities

design/clean rooms, water/

gas quality, HVAC, material

flow, maintenance and

calibrationenvironmental

and utilities

monitoring,

smoke studies

incoming /

Starting

materials

pre-assessment, URS,

specification,

agreements, testing

supplier

qualification

personnel

health, gowning, training /

education, behavior,

aseptic techniques,

personnel flow, access

control

material transfer

grade A continuity,

wrapping, autoclave

personnel

qualification

Key process

risk

assessments

e.g. EM

validation

(incl. APS) &

qualificationhouse-

keeping,

cleaning &

disinfection

trending

product

testing,

CQA

trending of

monitoring

data

disinfectant

validation

continuous monitoring /

governance

Management

Review, PQR

Self Inspection

management and

QA oversight,

Quality risk

management

audit,

monitorin

g

monitoring

and

trending of

data

trending

trending

CPV

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Quality Risk Management


• There are strict requirements

• Grade A / B and Grade C and D

– Air quality by viable, non-viable particles and

air flow pattern

– Minimum requalification interval

– Smooth surfaces

– No particle shedding materials

– Airlocks

– etc.

Nothing really new

Annex 1 special requirements for cleanroom classes address the critical risks of sterile

manufacturing - no variability by applying QRM

Apply Additional QRM Principles

• Define best clean room design for the process

• Evaluate movement of material and personnel in

the light of contamination and cross

contamination

• Requalify periodically and after changes of

equipment, facility or processes based on the

principles of QRM

BUT

16

Introduction


17

Clauses requiring comment related to concerns raised by stakeholders during the 2017 Public Stakeholder consultation.


Qualification and

re-qualification of

Cleanrooms

Integrity testing of large

volume parenteral

containers

Handling of Water

Systems

Sterility Testing

Handling of Sterilizing

filter including Pre-use

Post-use sterilization

integrity testing

(PUPSIT)

Handling of Lyophilizer

18

Clauses requiring comment related to concerns raised by stakeholders – Key Messages


Qualification and

re-qualification of

Cleanrooms

Integrity testing of

large volume

parenteral

containers

Handling of Water

Systems

• Take a phased approach to

from Classification (particulate

clean-up performance) into

qualification that verifies both

particulate and microbial

contamination levels do not

exceed set limits.

• Add clarity to requalification

requirements.

• Removal of 1µm particle size

• Apply principles of ISO14644*

• Not all water systems require

pyrogen control (e.g. Purified

Water).

• Text should be more line with

PhEur 10.0

• Containers closed by fusion,

e.g. Blow-fill-seal (BFS), Form-

Fill-Seal (FFS), Small and

Large Volume Parenteral

(SVP & LVP) bags, glass or

plastic ampoules, should be

subject to 100% integrity

testing.

• This is not feasible for all

presentations – should allow

other validated methodology.

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Clauses requiring comment related to concerns raised by stakeholders – Key Messages


Handling of Sterilizing

filter including Pre-use

Post-use sterilization

integrity testing

(PUPSIT)

Handling of Lyophilizer Sterility Testing

• Until capped, product removed from the

lyophilizer should remain under Grade

A conditions air supply

• Cf. 8.25 Finishing of sterile products

where grade A is required until capped?

• Sterility test: suggested to be taken

beginning, middle and end of the

batch and after any significant

intervention (e.g. open barrier door).

It is suggested that sampling

frequency should be justified and

documented in a CCS.

• Filtration - From the text in

section 8.82 it is difficult to

understand what the requirement

is and what the recommendation

is and what is good to have.

• Clarification is really needed to

prevent mis-interpretation. The

filtration of very small volumes of

solution is not the only case

where PUPSIT can add more

risks than benefits.

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PUPSIT – Not a new requirement, but new Regulatory Enforcement*

Historically, there are different positions

- Industry: Flaw masking is uncommon; PUPSIT adds risk,

may disrupt aseptic pathway, adds complexity and

interventions, stresses filter

- Regulators*: Flaw masking is a relevant risk. PUPSIT is

easy to implement, industry just does not want to do it.

Risk assessments can be biased

• NEED OF DATA & FACTS* Not all regulators have the same position

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PDA – BioPhorum:Sterile Filtration Quality Risk Management (SFQRM) consortium

Recommendations:

Masking

Trials

BCT* Data

Mining

Best

Practice

Risk

Assessment

* BCT: Bacterial Challenge Test

22

Clauses that were substantially changed following 2017 Public Stakeholder consultation.


Definition and Handling of

Barrier systems including

disinfection/

decontamination

Personal qualification and

gowningHandling of Gas Filters

Aseptic Process

Simulation (APS)

Aseptic production Personal Monitoring

Quality Control

Moist Heat

23

Clauses that were substantially changed – Key Comments


Definition and Handling of

Barrier systems including

disinfection/

decontamination

Personal qualification

and gowningHandling of Gas Filters

• Requirements state that personnel

working in grade C and D should go

through gowning qualification. Gowning

qualification of personnel working with

non critical activities in lower grade

cleanrooms should include training but

not full qualification based on the lower

risks.

• To restrict people entering – facilities

need to be better designed.

• Add clarity to differentiation

between RABs and Isolators

• Make clear differences between

RABs and Isolators and the

sterility assurance of in-direct

product contact parts

• Glove testing physical vs visual

inspection/campaign or batch

• Gases should be of

appropriate quality

• Should be tested as part of

campaign manufacture

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Aseptic production Moist heat

• Suggested the use of the principles and

measures taken shall be documented in the

CCS.

• Should reference the processes already

mentioned – use of barrier systems,

sterilisation-in-place, robotics etc and defined

in CCS

• The required Intervention list should in APS

section and not in aseptic production

• Needed differentiation between porous

loads, terminal sterilisation of

products/fluid cycles and steam-in-place

• Validation needs both minimum and

maximum temperatures attained

• Need a validated air detector with

periodic Bowie Dick for verification

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Personal Monitoring

• It is unclear what is intended by the

statement that “Particular

consideration should be given”.

Unclear whether the intent is to

include exit monitoring for all

personnel regardless of activity

• A requirement to monitor all

personnel entering the aseptic area

and in exit also introduces risk by

requiring additional presence of

personnel / sampling media.

Aseptic Process

Simulation (APS)

• Not a catch all - part of the sterility

assurance measures

• Frequency of interventions based upon

risk to process that cannot be detected

by other means

Quality Control

• 10.6 Point i. indicates in addition to

pulling sterility samples at the beginning,

middle, and end of a batch, to also pull

samples at a significant intervention (e.g.

interventions where the integrity of the

barrier is breached (open door)) or an

operator intervention into critical zones.

• Clarify lyo load Samples for sterility

testing.

26

Other Significant comments on Annex 1 sections together with update of Glossary


Disinfection EquipmentPremises

Dry HeatFinishing Sterilisation

Ethylene Oxide FFS & BFSEnvironmental Monitoring

EM

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Disinfection EquipmentPremises

• The requirement to have

different modes of action of

disinfectant is still included

• 4.11 The section describes that

transfer into an aseptic processing

area should be carried out via a

unidirectional process.

• The term 'unidirectional' used in this

context is confusing as it may be

interpreted as UDAF.

• 4.16 "A warning system should be in

place to instantly indicate and warn

operators of any failure in the air

supply or reduction of pressure

differentials…"

• Not all indirect contact parts can be

sterilised – needs have flexibility e.g.

when heat sterilization is not possible

(e.g. large built in stopper bowls in

isolators), surface disinfected with

automated processes based on low

bioburden and spore reduction to the

sterility assurance level.

• Direct contact parts are those that the

product passes through, such as filling

needles or pumps. Indirect product

contact parts are equipment parts that

come into contact with sterilized critical

items and components.“

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Dry HeatFinishing Sterilisation

• It is not clear if IPC testing for

products not closed by fusion

(e.g. vials, syringes) should be

performed per batch. If this is the

requirement, then it should be

clearly stated.

• Lacks clarity as most refers to terminal

sterilisation – but not clear

• Cycle review now part of batch

certification

• 8.34 All parameters should be defined,

and where critical controlled, monitored

and recorded.

• Need to understand what is critical

• 8.66 The description of dry

heat sterilisation is not accurate

and confusing.

• "8.67 Dry heat sterilizing/

depyrogenation tunnels should

be configured to ensure that air

flow protects the integrity and

performance of the Grade A

sterilizing zone by maintaining

pressure differentials and air

flow through the tunnel from

the higher grade area to the

lower grade area."

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FFS & BFSGaseous sterilisation

e.g. Ethylene Oxide

Environmental Monitoring

EM

• Requirements and guidance for

VHP decontamination are missing.

It is understood that this is not a

sterilization method (fully

penetrative) but a decontamination

method and that should be clear in

the Annex.

• But since VHP is a widely used bio-

decontamination method

requirements and guidance is

needed for this process to add

clarity on expectations. The MHRA

Blog ‘Fragility of VHP’ indicated the

need for Clarity.

• Form Fill Seal - There is a mix-

up between the Form-Fill-Seal

process and the Blow-Fill-Seal

process. They are two separate

techniques that should be

addressed separately. Most of

the requirement under the

heading "Form-Fill-Seal" does

not apply to Blow-Fill-Seal.

• Update section specifically for

VFFS to provide more clarity.

• BFS Grade A air conditions

should be Grade A air quality

• Viable and non-viable environmental and

process monitoring - (9.29) "Sampling

methods and equipment used should be fully

understood. The recovery efficiency of the

sampling methods chosen should be

qualified.“

• Location and type of media chosen

determined at facility PQ based upon design

and process knowledge and confirmed with

EMPQ

• Where processes have materials that

contact the product contact surfaces but are

then discarded, the discarded material

should be simulated with nutrient media and

be incubated as part of the APS.

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Thank You

Any Questions?

.

Industry Perspective on Annex 1

Documents

Industry Perspective on Annex 1...Pharmaceutical Manufacturing & Quality: Emerging Regulations and Their Impact Industry Perspective on Annex 1 Tuesday, 22. September 2020 Gabriele