1. CMC Biologics – Copenhagen Site
Cleaning Strategy of Multipurpose Equipment in GMP facilities
Evete Mawlad, 20Apr CONFIDENTIAL

2. CMC Biologics – Copenhagen Site
Introduction of CMC Biologics
Copenhagen Facility
Cleaning strategy
22 September 2018
CONFIDENTIAL

3. Cleaning Strategy
CONFIDENTIAL

4. Cleaning Strategy 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 Assessment
Support systems
Campaign Rationales
New EMA guideline
Acceptance criteria in CMC CPH today
Validation vs Verification
Cleaning Validation vs Verification
Cleaning Validation ….. Hold Time
Continually documentation- and evaluation of the cleaning process efficiency
22 September 2018
CONFIDENTIAL

5. The definition of Cleaning Validation
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. LeBlanc
The 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
22 September 2018
CONFIDENTIAL

6. The definition of Cleaning Validation…. continue
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
22 September 2018
CONFIDENTIAL

7. Requirements & guidelines
Code of Federal Regulations
PART CURRENT GOOD MANUFACTURING PRACTICE FOR FINISHED PHARMACEUTICALS,
Subpart D – Equipment (Sec ):
(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 CURRENT GOOD MANUFACTURING PRACTICE IN MANUFACTURING, PACKAGING, LABELING, OR HOLDING OPERATIONS FOR DIETARY SUPPLEMENTS
Subpart D--Equipment and Utensils (Sec )
(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.
22 September 2018
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8. Requirements & guidelines…continue
Code of Federal Regulations
PART QUALITY SYSTEM REGULATION
Subpart G – Production and Process Controls (Sec ):
(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)
22 September 2018
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9. Requirements & guidelines…continue
EudraLex - Volume 4 Good manufacturing practice for Medicinal Products for Human and Veterinary Use
Annex 15: Qualification and Validation, 30Mar2015
Sec. 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.
22 September 2018
CONFIDENTIAL

10. Requirements & guidelines…continue
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-contamination
1.6 Cleaning validation should be considered important in multiproduct facilities and should be performed among others, for equipment, sanitization procedures and garment laundering.
22 September 2018
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11. Requirements & guidelines…continue
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)
22 September 2018
CONFIDENTIAL

12. Why perform Cleaning Validation?
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? 
22 September 2018
CONFIDENTIAL

13. Why perform Cleaning Validation?....continue
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.
22 September 2018
CONFIDENTIAL

14. Why perform Cleaning Validation?....continue
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.
22 September 2018
CONFIDENTIAL

15. When to perform Cleaning Validation…?
New product (reg. requirement)
Cleaning agent modification/change
Critical change in a cleaning procedure
Equipment modification
Critical change in formulation
22 September 2018
CONFIDENTIAL

16. What is the cleaning process/flow?
Batch A
Manufacturing Batch A
Clean – (Line ChangeOver)
Batch B
Manufacturing Batch B
Batch X
Manufacturing Batch X
Prod A
Manufacturing Prod A
Clean – (ChangeOver)
Prod B
Manufacturing B
Prod X
Manufacturing Prod X
22 September 2018
CONFIDENTIAL

17. Generic Cleaning Method - Clean-in-place (CIP)
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 rinse
Acid 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.
22 September 2018
CONFIDENTIAL

18. FDA guideline for Process Validation
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
22 September 2018
CONFIDENTIAL

19. 22 September 2018
CONFIDENTIAL

20. New EMA guideline
“ 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 2015
Implementation 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.
22 September 2018
CONFIDENTIAL

21. New EMA guideline …continue
Permitted Daily Exposure (PDE)
Equivalent to the earlier used :
Acceptable Daily Exposure (ADE)
Acceptable Daily Intake (ADI)
Tolerable Daily Exposure (TDE)
22 September 2018
CONFIDENTIAL

22. New EMA guideline …continue
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.
22 September 2018
CONFIDENTIAL

23. New EMA guideline …continue
22 September 2018
CONFIDENTIAL

24. Acceptance criteria in CMC CPH today
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/dm2
where:
Doses
TDA Dose of the former product (A) produced in the equipment
MTDB - Maximum Dose of the upcoming product (B) to be produced in the equipment
Batch size – BZB of the upcoming product (B) to be produced
SF - set to 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 dm2
F is the factors at different steps in the process etc.
22 September 2018
CONFIDENTIAL

25. Acceptance criteria in CMC CPH today…continue
22 September 2018
CONFIDENTIAL

26. Validation vs Verification
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 (z)
Verification means confirmation by examination and provision of objective evidence that specified requirements have been fulfilled.
21 CFR (aa)
22 September 2018
CONFIDENTIAL

27. Cleaning validation/verification
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)
22 September 2018
CONFIDENTIAL

28. Cleaning Validation…Hold times
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.)
22 September 2018
CONFIDENTIAL

29. Thank you for your attention......
22 September 2018
CONFIDENTIAL