CMC Biologics – Copenhagen Site - PowerPoint Presentation

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CMC Biologics – Copenhagen Site

Cleaning Strategy of Multipurpose Equipment in GMP facilities Evete Mawlad, 20Apr2016 CONFIDENTIAL

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Introduction

of CMC BiologicsCopenhagen FacilityCleaning strategyCMC Biologics – Copenhagen Site

2 May 2016

2

CONFIDENTIAL

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Cleaning Strategy

CONFIDENTIAL

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Definition..What

are the requirements?Why perform Cleaning…?What is the cleaning process/flow?Overview of Cleaning Strategy

Generic Cleaning Method - Clean-in-place (CIP

)

FDA guideline for

Process

Validation

Cleanability

Risk

AssessmentSupport systemsCampaign RationalesNew EMA guideline Acceptance criteria in CMC CPH todayValidation vs VerificationCleaning Validation vs VerificationCleaning Validation ….. Hold TimeContinually documentation- and evaluation of the cleaning process efficiency

Cleaning Strategy

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The process of

removing contaminants from process equipment and monitoring the condition of equipment such that the equipment can be safely used for subsequent product manufacturing Dustin A. LeBlancThe process of providing documented evidence that the cleaning methods employed within a facility consistently

controls potential carryover

of product (including intermediates and impurities), cleaning agents and extraneous material into subsequent product to a level which is below predetermined

levels

in

the context of

API manufacture

The definition of

Cleaning Validation2 May 20165CONFIDENTIAL

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Documented evidence

that an approved cleaning procedure will consistently reduce active pharmaceutical ingredients (API), process residues, cleaning agents and microbial residues from product contact equipment surfaces to acceptable levels for the processing of drug products FDA; Guide to Inspections Validation of Cleaning Processes The definition of Cleaning Validation

….

continue

2 May 2016

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Code of Federal

RegulationsPART 211 --CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS, Subpart D – Equipment (Sec. 211.67):(a) Equipment and utensils shall be cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.

PART 111 --CURRENT

GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PACKAGING, LABELING, OR

HOLDING

OPERATIONS FOR DIETARY

SUPPLEMENTS

Subpart

D--Equipment and

Utensils

(Sec 111.27)(d) You must maintain, clean, and sanitize, as necessary, all equipment, utensils, and any other contact surfaces used to manufacture, package, label, or hold components or dietary supplements.Requirements & guidelines2 May 20167CONFIDENTIAL

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Code of Federal Regulations

PART 820 -- QUALITY SYSTEM REGULATIONSubpart G – Production and Process Controls (Sec. 820.70):(e) Contamination control: Each manufacturer shall establish and maintain procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality.Guide to Inspections of Validation of Cleaning Processes (1993)

Requirements &

guidelines…continue

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EudraLex

- Volume 4 Good manufacturing practice for Medicinal Products for Human and Veterinary UseAnnex 15: Qualification and Validation, 30Mar2015Sec. 10 Cleaning validation: Cleaning validation should be performed in order to confirm the effectiveness of any cleaning procedure for all product contact equipment.

Pharmaceutical

Inspection Convention (PIC/S), Recommendations on…Cleaning

Validation(2007)

Pharmaceutical products and active pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by micro-organisms or by other material (e.g. air-borne particles, dust, lubricants, raw materials, intermediates, auxiliaries). In many cases, the same equipment may be used for processing different products. To avoid contamination of the following pharmaceutical product, adequate

cleaning procedures are essential.

Requirements & guidelines…continue

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WHO Technical

Report No. 937: WHO Supplementary Guidelines on GMP (Annex 4 ): Validation (2006)Appendix 3, Cleaning validation: 1.4 The objective of cleaning validation is to prove that the equipment is consistently cleaned of product, detergent and microbial residues to an acceptable level, to prevent possible contamination and cross-contamination1.6 Cleaning validation should be considered important in multiproduct facilities and should be performed among others, for equipment, sanitization procedures and garment laundering.

Requirements & guidelines…continue

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And more……

FDA Guidance for Industry Process validation: General Principles and Practices (January 2011, Revision 1) ICH Q7 – Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. November 2000. PDA Technical report No. 29, Points to Consider for Cleaning Validation PDA Technical report No 49, Points to Consider for Biotechnology Cleaning Validation (2010) Requirements & guidelines…continue

2 May 2016

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The reasons are:

The FDA/EMA/DHMA or any other agencies won’t approve my/your product

Job Security

QA

said

so…

Because

it is

fun

?

Why perform Cleaning Validation?2 May 201612CONFIDENTIAL

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It is regulatory requirement

in pharmaceutical product manufacture the concern is the same-assurance that equipment is clean and that product quality and safety are maintained To check the effectiveness of the cleaning procedure for equipment’s used in manufacturing of the Drug Product T o verify for removal of Previous Batch, Cleaning Agents Residue and Potential Microbial Contaminants

It

assures from an internal control and compliance point of view for the quality of product

.

Why perform Cleaning Validation

?....continue

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In 1988, FDA had its

first major experience with cross contamination traceable to inadequate cleaning and cleaning validation. An API supplier of Cholestyramine Resin recall the product, due to contamination with low levels of intermediates and degradants from the production of agricultural pesticides. This

cross-contamination attributed to drums used to recover solvent from agricultural pesticides manufacture at another location. The drums were not properly cleaned leading to agricultural pesticides entering the API manufacturing process.

Why perform Cleaning Validation?....continue

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New product (reg. requirement)

Cleaning agent modification/changeCritical change in a cleaning procedureEquipment modificationCritical change in formulationWhen to perform Cleaning Validation…?

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What is the cleaning process/flow?

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A typical CIP cycle consists of….:

Pre-rinse with WFI (water for injection) or PW (purified water)Caustic solution is the main cleaning solution.Caustic solution re-circulation Intermediate WFI or PW rinseAcid solution wash used

to remove mineral precipitates and protein residues.

Final rinse with WFI or PW – rinses to flush out residual cleaning agents.

Final air blow – used to remove moisture remaining after CIP cycle.

Generic Cleaning Method - Clean-in-place

 (

CIP

)

2 May 2016

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The cleaning strategy and requirements follows the FDA guideline for Process

Validation covering the lifecycle approach for the three stages:Stage 1 – Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing.

Stage

3 – Continued Process Verification:

Ongoing assurance is gained during routine production that the process remains in a state of

control

FDA

guideline for Process Validation

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2 May 2016

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“ Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities “

Effective date for the guideline : 1. June 2015Implementation Plan:1) New products:For medicinal products introduced for the first time into shared manufacturing facilities: 6 months from publication of this guideline. 2) Existing products:1 year after publication of the guideline for manufacturers of products for human use including those who manufacture human and veterinary medicines using shared manufacturing facilities.

New EMA guideline

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Permitted Daily Exposure (PDE)

Equivalent to the earlier used : Acceptable Daily Exposure (ADE)Acceptable Daily

Intake

(ADI)

Tolerable

Daily

Exposure

(TDE)

New EMA guideline

…continue2 May 201621CONFIDENTIAL

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Permitted Daily Exposure (PDE)

where NOAEL is no-observed-adverse-effect level Weight Adjustment is the body

weight

(

nomally

for adult: 50 Kg)

F1, F2, F3, F4 and F5

are

safety factors pending of species, length of the studies, route of administration etc. – the factors can be between 1- 12 pending on which factor to estimate.New EMA guideline …continue2 May 2016

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New EMA guideline …

continue2 May 201623CONFIDENTIAL

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Acceptance

criteria is based on the principle for Maximum Allowable Carry Over (MACO

) of active product A

to

product

B:

Acceptance

criteria

= (MACO/SA) x F mgC/dm2where:DosesTDA - Dose of the former product (A) produced in the equipmentMTDB

- Maximum Dose

of the upcoming product

(B) to be produced in the

equipment

Batch

size

–

BZ

B

of the

upcoming

product

(B) to

be

produced

SF -

set to 1000 - max 1/1000 of a

dose

will

be

entered

in the

next

product

dose

Shared

equipment

surface

– SA -

is the

equipment

surfaces

shared

between

the former

product

(A) and the new

product

(B) in dm

2

F

is the factors at

different

steps in the

process

etc.

 

Acceptance

criteria

in CMC CPH

today

2 May 2016

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Acceptance

criteria in CMC CPH today…continue2 May 201625

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Validation

means confirmation by examination and provision of objective evidence that the particular requirements for a specific intended use can be consistently fulfilled.21 CFR 820.3 (z)Verification

means confirmation by examination and provision of objective evidence that specified requirements have been fulfilled.

21

CFR 820.3 (

aa

)

Validation

vs

Verification

2 May 201626CONFIDENTIAL

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To

avoid cross contamination from one production to another and build up between batches in a campaign Cleaning validation performed no later than during process Performance Qualification, PPQ for product for commercial production

Parameters:

Visual inspection

Conductivity (cleaning agent residues)

Bioburden

Endotoxin

TOC (rinse- and swab samples)

Cleaning validation/verification

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Dirty Hold Time: Time between end of manufacture and beginning of cleaning.

Why..? Manufactured product will become harder to clean (dries, bio-burden growth )Clean Hold Time: Time from end of cleaning to beginning of manufacture Why..? Equipment may become re-contaminated during storage ( bio-burden , dust etc.)Cleaning Validation…Hold times

2 May 2016

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Thank you for your attention......

2 May 201629CONFIDENTIAL