# Presentation: 364266

## Plasma Derivatives: Cleaning Procedures and Clearance of TSE Agents During Manufacturing

**TSE Advisory Committee**
**July 18, 2003**
**Dorothy Scott, M.D.**
**Laboratory of Plasma Derivatives/OBRR/CBER**

## Use of Common Equipment for Manufacturing of U.S. and European Plasma for Plasma Derivatives in the Context of vCJD Risk

- Many manufacturers use common equipment for U.S. and European plasma
- Approved to do so as part of license or licensing supplements
- Products include: IGIV, albumin, FVIII, FIX
- At least 5 major manufacturers of plasma derivatives are licensed to use common equipment and facilities for U.S. and European plasma
- vCJD donor deferrals differ between U.S. and European countries

## Recommended Plasma Donor Deferrals in U.S.

- 			_U.K._		_France_	_Europe_
- U.S.: SP1		_>_ 3 mos.	_>_ 5 years	no deferral
- U.S.: RP2		_>_ 3 mos.	_>_ 5 years	_> _5 years
- Europe3 		0 – 5 yrs.	0 – 6 mos 	no deferral
- Europe EMEA4	1 year		none 		none

-  and Europe for vCJD risk

**1**** Source Plasma; ****2**** Recovered Plasma; ****3**** Plasma; ****4**** EMEA CPMP Position Statement **
**on CJD and plasma-derived and  urine-derived medicinal products 2/2003 **
**(**_[http://www.emea.eu.int/htms/human/tse/tse.htm](http://www.emea.eu.int/htms/human/tse/tse.htm)__). _

##  Considerations in the Context of Risks of TSE Transmission via Reused Equipment and Materials

- Amount of agent in starting material (plasma)
- Presence and titer in plasma
- Deferral of at-risk donors
- Clearance (or concentration) by manufacturing processes
- Evaluation of the cleaning procedure for potential chemical inactivation of TSE agents should consider these influences on overall risk

## Reasons to Consider Decontamination of Facilities and Equipment for Plasma Derivatives

- Possibility that cross-contamination could occur; donor may be diagnosed too late to interdict plasma use
- Unpredictability of  human TSE outbreaks – possibilities for the future
- More BSE countries continue to be identified (e.g. Canada)
- In theory, prion codon 129 heterozygotes could develop vCJD (this would increase epidemic size)
- Chronic wasting disease in U.S. – spread to humans or domestic animals not impossible
- Analogous and connected to importance of continuing food chain controls

## http://www.who.int/csr/disease/bse/surveillance/en/

## Source Plasma 

- European risk of vCJD continues to be low (small BSE epidemic relative to U.K.)
- French risk perceived as higher due to greater number of vCJD cases, and British beef importation
- Model TSE agents partitioned/removed during plasma fractionation (TSEAC 2/2003)
- Source vs. recovered plasma- differentiated to prevent potential errors in use of deferred non-plasma components

## Slide 8

## vCJD Cases in Europe

- France (6)
- Italy (1)
- Ireland (1)
- (Czech Republic?) (1)
- Post-donation diagnosis of vCJD in a European donor is possible where plasma derivatives will have been processed

## TSE infectivity clearance during plasma derivative manufacturing

- Manufacturing steps that can result in TSE clearance
- Precipitations
- Depth filtration
- Column Chromatography
- Clearance is process and manufacturer-specific (because it is context-specific)
- Manufacturers invited to submit clearance data to FDA for consideration of labeling claims (TSEAC 2/20/2003 at http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3923t1.htm

## Cleaning Procedures Between Plasma Batches (Campaigns)

- Validation of equipment cleaning procedures is standard for licensure (but validation not TSE-specific)
- Examples of cleaning methods
- NaOH and/or NaOCl solutions
- Rinsing
- Examples of cleaning validation test methods
- Residual total organic carbon
- Residual protein
- Ionic strength of final rinsing solutions

## Equipment and Process Materials in Plasma Derivative Manufacturing

- Usually reused after cleaning:
- Plasma pooling equipment
- Stainless steel tanks
- Tangential flow filters*****
- Gaskets and tubing
- Sterile filtration/final filling machinery
- Affinity chromatography columns*****
- Some resins*****
- Usually Disposable:
- Sterile filters
- Depth filters
- Some resins (e.g. anion, cation exchange columns)

******* **Dedicated to U.S.-source plasma

## Chromatographic Column Retention of TSE Infectivity

**Foster, PR et al, Vox Sang 2000 78:86-95**
_**Resin**_**	****	****	**_**Product/Intermediate**_**	**_**RF**_*****
**S-Sepharose****	****	****	****Thrombin****	****	****2.9**
**(cation exchange)**
**Heparin-sepharose****	****	****FIX****	****	****	****1.4**
**(affinity)**
**DEAE Sepharose****	****	****FIX****	****	****	****3.0**
**(anion exchange)**

**Logs reduction Prp-sc by Western blot = **_**titer spiked intermediate/**_
**                                                                         ****titer of resultant fraction **

## Chromatographic Column Retention of TSE Infectivity

**Foster, PR et al, Vox Sang 2000 78:86-95**

**“****Only a small proportion of Prp-sc could be **
** ****accounted for in samples taken over chromatographic**
** ****procedures, e.g. about 0.1%”**
**“****The probability that most Prp-sc remained bound to **
** ****chromatographic matrices emphasizes the importance**
** ****of either limiting the re-use of adsorbents or in **
** ****developing suitable cleaning procedures.”**

## TSE Adherence to Chromatographic Resins

- Demonstrated in other published studies: _10__**2**__ – 10__**5**__ fold reduction in scrapie infectivity_
- Hunter and Millson (J. Gen. Microb. 37:251-8)
- Kozak et al (Dev. Biol. Stand. 88:257-64, 1996)
- Blum et al (Biopharm. 11:28-34, 1998)
- Reported for anion exchange, cation exchange, hydrophobic interaction, and affinity chromatography
- Some chromatographic resins (e.g. some anion, cation) may be washed with 0.1-1 M NaOH; others (e.g. antibody affinity columns and hydrophobic interaction columns) are not chemically stable under alkaline conditions

##  Considerations in the Context of Risks of TSE Transmission via Reused Equipment and Materials

- Amount of agent in starting material (plasma)
- Presence and titer in plasma believed to be low, if present
- Deferral of at-risk donors from the U.K., in particular, limits the number of possible incubating donors
- Clearance by manufacturing processes
- Demonstrated in general for many common procedures used in plasma derivative manufacturing; submission of rigorous and process specific studies to FDA requested on a voluntary basis
- Evaluation of cleaning for TSE agents should consider these influences on overall risk

## Questions to the Committee: Plasma Derivatives

- 1.  Are current facility cleaning methods, e.g. the use of solutions of sodium hydroxide or sodium hypochlorite followed by extensive rinsing cycles, **adequate to minimize the possibility** that an infectious dose of the vCJD agent may be carried over from one manufactured lot into the next?

## Questions to the Committee: Plasma Derivatives

- Are the available scientific data sufficient for FDA to recommend specific methods for cleaning of equipment used in the manufacture of plasma derivatives with respect to TSE clearance or inactivation?
**If so, please identify which methods can be recommended**
**b.   If not, please describe what additional studies would assist in development of such recommendations**

## Speakers: Methods to Decontaminate Facilities and Equipment for Plasma Derivatives, to Reduce Possible Risk of TSE Transmission

- Decontamination Practices for Plasma Product Facilities
- Dr. Cristoph Kempf, PPTA (Plasma Protein Therapeutics Association)
- Proposed PPTA-sponsored Collaborative Studyon Inactivation of TSE Agents with Sodium Hydroxide and Sodium Hypochlorite, Commonly Used to Clean and Decontaminate Facilities and Equipment in Manufacture of Plasma Derivatives
- Dr. Andrew Bailey, PPTA