GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS - SECTION 1

JUNE 1997
(Apr 2001 - Editorial Revisions)

NOTE: This document is reference cloth for Investigators and other FDA personnel. The document does not bind FDA, and does not confer any rights, privileges, benefits, or immunities for or on any person(s). An alternative arroyo may be used if such an approach satisfies the requirements of the applicable statues, regulations, or both.

TABLE OF CONTENTS

Department 1
Introduction
General Data
Operations
Standard Operating Procedures
Errors, Accidents and Fatalities
Adverse Reaction
Lookback
Plasmapheresis Facilities
Equipment
Medical Device Reporting
Medical Supervision

SECTION two
Donor Identification
Informed Consent
Initial Medical Exam
Immunization
Donor Suitability
Infrequent Donations
Blood Collection
Donor Record Files
Plasma Separation and Pooling (Manual Merely)
Reinfusion of Cherry Blood Cells (Transmission Collection)

SECTION iii
HBsAg, Anti-HCV and Anti-HIV Testing
Handling of HBsAg, Anti-HCV and Anti-HIV Repeatedly Reactive Units
Serum Protein Quantitation
Serologic Exam for Syphilis
Storage
Distribution Record
Disposal of Infectious Waste product
Computerized Records
Disease State Donors
"Loftier Adventure" Donors
Source Leukocytes
Therapeutic Exchange Plasma

Section 1
INTRODUCTION

This guide, which provides the well-nigh updated estimation of sure regulations and guidelines, was prepared past the FDA, Part of Regulatory Affairs (ORA) and the Center for Biologics Evaluation and Enquiry (CBER). This guidance represents the Agency'south electric current thinking regarding the inspection of source plasma establishments. Information technology does non create nor confer whatsoever rights for or on whatever person and does not operate to bind FDA or the public. An alternative approach may be used past industry if such approach satisfies the requirements of the applicable statute, regulations, or both.

This guide is intended to be used in conjunction with the FDA/Investigations Operations Manual (IOM); the Lawmaking of Federal Regulations, Championship 21 (21 CFR); the Compliance Program for the Inspection of Source Plasma Establishments (CP 7342.002); and the Compliance Policy Guides (CPG) for Biologics, which are contained in Affiliate 2 of the Compliance Policy Guides Manual.

Current guidance documents and prior blood memoranda published by CBER may be available at the FDA District Offices or a copy tin exist obtained through the CBER FAX Information System, i-888-CBER-FAX , or past accessing the CBER abode page at http://www.fda.gov/cber/guidelines.htm.

The preparation of products for which there are no additional standards published in the Code of Federal Regulations (CFR) must exist described in the institution'south standard operating procedures (SOP) manual and manufactured in accordance with the methods therein. Questions concerning the data independent in this guide should exist addressed to CBER, Segmentation of Inspections and Surveillance, Plan Surveillance Co-operative (HFM-654) at 301-827-6220 , or the ORA/ORO Sectionalisation of Emergency and Investigational Operations at 301- 827-5653.

General Information

Investigators should asking to see the firm's approval letter of the alphabet to manufacture Source Plasma, Source Leukocytes or Therapeutic Commutation Plasma and the alphabetic character that assigned a U.S. License Number to the house. CBER assigns a license number after approval of the showtime biologic license awarding. The blessing letter identifies the products that may be delivered or introduced for delivery into interstate commerce and the license number must appear on the product label. The license number serves to place establishments in correspondence, applications, and other forms of communication.

The investigator should also review the establishment's validated re-create of Class FDA-2830, Blood Establishment Registration and Product List, for the electric current calendar twelvemonth or if evidence exists, that the firm submitted information technology to FDA. If the information on the registration class is non right, report the corrections to be fabricated in the EIR, and instruct the establishment to submit, in writing, the updated information to the CBER, Sectionalisation of Blood Applications, (HFM-370), 1401 Rockville Thruway, Rockville, Doctor 20852-1448. Establishments should written report changes in their proper noun, address or products to the Division of Claret Applications. They should submit these changes in a supplement to their biologic license. Establishments should notify CBER of changes in the Authorized Official past letter.

OPERATIONS

Determine whether Source Plasma is collected for utilise in manufacturing licensed injectable products, licensed in vitro diagnostic products, or unlicensed products.

Determine from whom Source Plasma is being nerveless: normal donors, immunized donors, disease associated, affliction state or high-chance donors. Donors may have pre-existing antibodies or may have been sensitized to produce specific antibody(s) in an immunization program. Describe what affliction states are applicable. Determine what products other than Source Plasma are beingness collected, for example Source Leukocytes or Therapeutic Commutation Plasma. Source Plasma, Source Leukocytes and Therapeutic Exchange Plasma are is subject to the licensure provisions of Section 351 of the Public Wellness Service Act and may only be shipped in interstate commerce if the Source Plasma manufacturer has an unsuspended and unrevoked U.S. License.

In Oct 1997 the final rule on changes to an canonical application became effective. Changes may exist made in ane of three categories based on the potential of the change to take an agin effect on the identity, strength, quality, purity and say-so as they relate to the safety or effectiveness of the product. For further information regarding reporting changes refer to 21 CFR 601.12, and the CP7342.001 - Inspection of Licensed and Unlicensed Blood Banks, Brokers, Reference Laboratories, and Contractors.

Non all procedures are reviewed and canonical by CBER. CBER approval letters should be bachelor for review during the inspection. CBER does not review and approve all procedures, therefore, if an investigator observes a procedure that is considered unsafe for the donor or that may touch on the safety, purity, or authorization of the product, contact the Division of Inspections and Surveillance (HFM-654) at 301-827-6220 .

STANDARD OPERATING PROCEDURES

A Source Plasma establishment should submit a supplement to its biologic license application when making changes to the post-obit SOPs: donor suitability, arm grooming for phlebotomy, AIDS educational information materials, donor history records, including informed consent forms, component preparation, and disposition of unsuitable products. The firm should have a mechanism for maintaining SOPs, and the SOPs should be readily available to the personnel performing the work in each surface area of manufacturing.

In that location should be a written procedure to minimize the spread of infectious agents, and it should exist consequent with current CDC and OSHA recommendations. OSHA published the final rule for the "Occupational Exposure to Bloodborne Pathogens" in the December 6, 1991, Federal Register. Included in the rule are requirements for facilities to develop procedures to ensure the rubber of employees with a potential for exposure to biohazardous materials and procedures for medical waste disposal. Precautions that routinely may be followed include wearing gloves and protective article of clothing as well as providing vaccination confronting Hepatitis B. Masks and face or eye coverings or a shield may likewise be used if the likelihood of exposure to infectious agents increases and represents a take a chance. Investigators should discuss these problems with the house at the close of the inspection.

ERRORS, ACCIDENTS AND FATALITIES

Licensed establishments are required to report to the Director, Function of Compliance and Biologics Quality (OCBQ), CBER, all errors and accidents in manufacturing which may impact the safety, purity, or authority of any product. CBER requires that this information exist submitted through the Error and Accident Reporting system. In the March xx, 1991, memorandum, "Responsibilities of Claret Establishments Related to Errors and Accidents in the Manufacture of Claret and Claret Components," unlicensed, registered establishments are requested to voluntarily report errors and accidents. Reports should be submitted promptly after errors and accidents are discovered. Errors or accidents that may affect the prophylactic, purity, or authorisation of a product include, but are not limited to, the release of the following:

  • units repeatedly reactive to viral marker testing;
  • units from donors for whom exam results were improperly interpreted or improperly performed;
  • units from donors who are (or should have been) either temporarily or permanently deferred due to medical history or to a history of repeatedly reactive results to viral marking tests;
  • units prior to completion of all tests;
  • incorrectly labeled components;
  • product incorrectly stored (e.g., incorrect storage/aircraft temperature).

Establishments that perform their own testing or contract out testing should report errors and accidents to CBER. Contract testing laboratories should promptly notify client establishments of errors in testing so that plasma establishments may take advisable action on distributed products promptly. The client plasma establishment should determine if an error/blow report to CBER is necessary and/or if retrieval of production is necessary.

Refer to the March 20, 1991, memorandum, "Responsibilities of Claret Establishments Related to Errors and Accidents in the Manufacture of Blood and Blood Components," for additional guidance.

Special attention should be given to any drove-related fatality that occurred since the previous inspection. Fatalities are to be reported to CBER's Office of Compliance and Biologics Quality using one of the post-obit options: (1) Telephone number 301-827-6220 ; (2) Eastward-mail address "fatality@cber.fda.gov"; or (3) Fax number 301-827-6748 . In the issue that an FDA investigator becomes aware of a previously unreported collection-related fatality, CBER's Sectionalization of Inspections and Surveillance (HFM-650) should be notified as soon as possible at 301-827-6220 .

Agin REACTIONS

Every agin reaction experienced by the donor, whether considered insignificant or astringent, must be recorded by the firm. All donor agin reactions must be recorded in the donor'southward record; a separate adverse reaction file may also exist maintained by the house. The agin reaction should be satisfactorily documented by donor middle personnel, including measures taken to aid the donor and the resolution of the reaction, and it should be noted every bit having been evaluated by the licensed physician or physician substitute. Reactions, including only non express to, lightheadedness, fainting, nausea, tingling, flushing, wheezing, chest pain, low blood pressure, rapid heart rate, low dorsum pain, bronchial spasms, difficulty animate, loss of consciousness, and convulsions, should be evaluated by the medico/physician substitute. Reactions at the site of injection may include infection, itching, and hematoma. The Draft Reviewers' Guide "Informed Consent for Plasmapheresis/Immunization" provides additional information on possible reactions. Follow-up instructions regarding donor care should also be added to the documentation of the reaction. In those cases where a donor has required prolonged ascertainment, emergency transportation, or hospitalization, the donor record file (DRF) should include appropriate notation and medical blessing by the physician (not the medico substitute) for the donor to continue participating in whatever program the donor is qualified. The procedure describing this evaluation should be in the SOP.

Wrong cherry blood cell infusions and associated fatalities if any should be documented past the firm and associated fatalities (if whatever) reported to CBER/Partitioning of Inspections and Surveillance (HFM-650). Records relating to the incident must exist maintained and made a part of each affected donor's record. Complications of blood drove that result in a fatality are the only donor reactions that Source Plasma establishments are required to report to CBER. The SOP should address procedures for documenting the fatality and required reporting.

LOOKBACK POLICY

Refer to the April 23, 1992, memorandum "Revised Recommendations for the Prevention of Human Immunodeficiency Virus (HIV) Transmission by Blood and Blood Products" for additional guidance. Too encounter the FDA concluding rule, Current Good Manufacturing Practices for Claret and Blood Components: Notification of Consignees Receiving Blood and Blood Components at Increased Take a chance for Transmitting HIV Infection, effective November viii, 1996. For Hepatitis see "Recommendation for the Quarantine and Disposition of Units from Prior Collection from Donors with Repeatedly Reactive Screening Tests for Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and Human T-Lymphotropic Virus Type I (HTLV-I)" dated July xix, 1996.

Refer to CBER's guidance for industry titled "Current Good Manufacturing Practice for Blood and Claret Components: (1) Quarantine and Disposition of Units from Prior Collections from Donors with Repeatedly Reactive Screening Tests for Antibody to Hepatitis C Virus (Anti-HCV); (two) Supplemental Testing, and the Notification of Consignees and Blood Recipients of donor Examination Results for Anti-HCV, " dated September 1998, or the virtually current guidance certificate.

PLASMAPHERESIS FACILITIES

All rooms and work areas where manufacturing operations are performed must meet CGMP regulations, including orderliness, cleanliness, lack of clutter, good lighting and ventilation, and are free from insects/vermin. Hand washing facilities for personnel should be conveniently located; soap, towels, and hot water should be available. If the sink is not in the same room every bit the donor drove area, it should be in the immediate vicinity. Bath facilities should be close enough that donors and personnel may easily reach them.

In facilities that include laboratories for testing for infectious agents, a separate room for laboratory procedures is recommended. Nonetheless, a specific expanse designated for infectious agent testing that is clearly labeled every bit such, is adequate. Testing laboratories should discover recommendations as published in the Centers for Affliction Control and Prevention (CDCP) and the National Institutes of Health (NIH) publication entitled "Biosafety in Microbiological and Biomedical Laboratories." The publication is available through the Department of Health and Homo Services (DHHS). It is publication No. (CDC) 88-8395, 94-95, 2nd Edition, Washington D.C.: U.S. Regime Printing Office, 1988.

EQUIPMENT

During the grade of an inspection, the investigator may discover or review instances where equipment or supplies are misused or not functioning as designed. Donor, operator, or product safety may exist compromised when equipment is misused or SOPs and/or manufacturer instructions are non followed. Information technology is important, therefore, that the house's equipment and supplies exist inspected, stored, maintained, calibrated, and used according to the manufacturer's supplied instructions. All equipment should perform in the manner for which it was designed and intended for utilise. A record relating to problems attributed to equipment and defective soft goods should be kept. Refer to the Source Plasma Compliance Program for specific instructions regarding documentation of deficiencies relating to the misuse of equipment.

Equipment should be calibrated using devices that have been compared to known standards, i.e. National Institute of Standards and Engineering (NIST), prior to initial use, after repairs, when advisable, and on a regularly scheduled basis as prescribed in the SOPs, the manufacturer'south specifications and the regulations. Records of such activities shall exist maintained.

The standardization and scale of the microhematocrit centrifuge may be washed with a commercially prepared control or by other methods, e.g., duplicate samples tested at multiple intervals. Utilize of capillary tubes, however, should follow manufacturer's instructions. The timer should be checked every three months.

Scales : Procedures should include performance checks of all scales used in blood drove, i.due east., trip scales and platform scales. Calibration should be done as necessary, with advisable records maintained. Regular quality control procedures for each automated drove device should include checking the scale with external standard weights to verify accuracy of the electronic scale.

Refractometer : Distilled water should be used to standardize the refractometer to the "nix" point. Certain manufacturer'due south instructions may specify that a suitable protein-based command with a refractometer reading of 6-viii gm/dl be used as a quality control check. Records must be maintained for daily standardization and for calibration in the event that the expected readings are non obtained. Serum or plasma is a sticky substance, and the surface of the refractometer should be cleaned immediately after each use with distilled H2o. An aqueous disinfectant (1:100 bleach to water) may exist used to disinfect the surface of the refractometer once the plasma is removed. If the prism of the refractometer is wiped merely with dry out material, information technology becomes scratched and may touch on its suitability for use. Alcohol should not exist used since it precipitates plasma protein and leaves a residue.

Refractometer results should be able to exist clearly read. Intendance should be taken to let the serum or plasma to flow over the prism, rather than touching the capillary directly on the prism. Extensive scratching of the refractometer prism may result in a "fuzzy" or "blurred" reading. A value for poly peptide concentration is obtained by looking through the eyepiece and noting where the sharp boundary between dark and light fields crosses the advisable scale (gm/dl). Precipitous contrast can merely exist verified by looking into the refractometer. The manufacturer's instructions for loading sample and reading results should exist followed.

Autoclave : Periodic performance checks are necessary to assure that the times and temperatures being recorded are acceptable for sterilization. Procedures should provide for scheduled scale as necessary, including before initial use and after repairs. Scale procedures should provide assurance that the autoclave functions as intended, i.e., sterilization of arm preparation supplies and/or decontamination of biohazardous material.

Biological indicators should exist used periodically and temperature indicators, such equally heat sensitive tape, should exist used with each run to verify that the materials are being sterilized. A minimum of 121.5° C (251° F) for threescore minutes by saturated steam at a pressure of 15 atmospheres is recommended for materials contaminated with blood; 20 minutes at the same temperature is recommended for arm preparation supplies.

Electronic Devices for Obtaining Vital Signs : When electronic devices (e.thou., IVAC) are used for blood pressure level, pulse, and temperature determinations, the firm should develop a quality control procedure to assure the device is functioning properly. The performance check of the device should be done periodically and should not exist limited just to the electronic check for the temperature function. In addition to performance checks, the blood pressure device should be calibrated, and the thermometer function should exist checked for accuracy.

Drove Containers : Only FDA-approved claret collection containers (with proper amount of anticoagulant) should exist used. Currently approved blood collection containers with anticoagulant (except heparin) for manual apheresis are manufactured by Baxter, Medsep, and Terumo. For more contempo approvals, contact the Division of Blood Applications (HFM- 370), 301-827-3524 . Claret drove containers shall exist checked for defects prior to use, and a method must be in place to relate the collection container to a donor.

Only FDA-approved administration/transfer sets and plasma containers should exist in apply.

Separated reddish claret cells may be diluted and resuspended only in 0.85% to 0.9% Sodium Chloride Injection, USP, which can too be used to keep the intravenous line and needle complimentary from clots.

The most frequently used anticoagulant for manual and automated apheresis is 4% Sodium Citrate. Other commonly used anticoagulants are citrate dextrose solution (ACD) and citrate phosphate dextrose (CPD). Collection in other anticoagulants or changes in formulation from that in 21 CFR 640.64 require CBER approving of a license or license supplement.

AUTOMATED APHERESIS EQUIPMENT - In a review of license applications, CBER considers an operator to device ratio of i:vi for trained staff and 1:iv during training equally acceptable. The ratio at luncheon and break periods should not differ from other times. Still, investigators should evaluate the competency of the staff and whether they are adequate in number. In addition CBER recommends that a fully trained operator be available as a back-up in the event problems arise.

The amount of plasma to exist collected is device-specific and based on the device manufacturer's approved nomogram or the FDA abbreviated nomogram, either of which must also be a function of the establishment's SOP. Refer to CBER memorandum titled, "Volume Limits for Automated Collection of Source Plasma," dated November four, 1992.

Operator training is essential in ensuring the appropriate and safe use of automated plasmapheresis devices. The content of the preparation program should include troubleshooting and trouble-solving of common issues that occur with the device. Once bones training has been completed and documented, a program for periodic updating and reassessment of operator skills, with appropriate documentation, should be in place.

A log for each device must be maintained and must (606.160) include the identity of the operator when the device is used. The device log should include the following for each solar day of use: all alarm messages received by blazon; all disposable equipment failures (due east.thousand., leakage and breakage); musical instrument failures (e.yard., electronics); all donor reactions, regardless of perceived significance; and any other problems noted. The maintenance and repair records of each separate automated drove device in use may provide bear witness of problems or failures and cosmetic actions taken.

Daily prepare-up of the device shall include a weight scale cheque using a known weight. Earlier the device is initially placed into use and after repairs, there should exist documentation of satisfactory performance of the device. There should be a record of functioning checks, the results of whatever problems discovered, and the identity of the operator performing the checks. Bug should exist satisfactorily resolved as evidenced by documented review. A plan of periodic preventive maintenance must also be written and followed by the establishment. Preventive maintenance plans are generally written by the manufacturer of the plasmapheresis equipment.

In that location should exist a system to ensure that the maximum time for saline assistants and/or anticoagulant fix up does not exceed 4 hours. There is a run a risk of bacterial contagion in one case the pocketbook of saline or anticoagulant is entered to connect the solutions to the apheresis prepare. 4 hours is considered the maximum time period that these solutions should be connected prior to product donor collection.

MEDICAL DEVICE REPORTING (MDR)

A Source Plasma manufacturer who also manufactures a medical device is field of study to the Medical Device Reporting (MDR) regulations, 21 CFR 803. The MDR regulations require that manufacturers of medical devices and certain types of medical institutions report whatsoever death or serious injury that a medical device may have caused or which was identified as being a contributing gene to the decease. Device manufacturers are likewise required to report device malfunctions that are likely to crusade or contribute to a death or serious injury if they were to recur. Device manufacturers and user facilities are required to institute and maintain written MDR procedures and MDR effect files consequent with 21 CFR 803.17 and 803.18 respectively. Device manufacturers should report all reportable deaths, serious injuries and malfunctions to FDA inside the time menstruation specified in the MDR regulations.

Medical institutions, such as hospitals, nursing homes, ambulatory surgical facilities, and outpatient diagnostic or treatment facilities are referred to as user facilities and are likewise subject to the MDR regulations [21 CFR 803.3(f)]. A user facility that includes a Source Plasma collection operation must report a death or serious injury to one of its patients if an automated collection device used by the Source Plasma operation contributed to the expiry or serious injury.

Inside ten days, user facilities must study all deaths to FDA and to the device manufacturer, if known. Within ten days, they must as well report a serious injury to the device manufacturer or if the device manufacturer is not known, to FDA. User facilities should report complaints related to the identity, quality, durability, reliability, safety, effectiveness or performance of a device to the device manufacturer. Issues with a device eastward.one thousand., a product defect or malfunction may also be reported directly to the FDA.

On a semiannual basis, user facilities must submit to FDA a summary of all MDR reports submitted to FDA and/or device manufacturers during the reporting period (21 CFR 803.33).

If a complication of blood collection is confirmed to be fatal, the Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Inquiry must also exist notified in accordance with 21 CFR 606.170(b). This requirement is in addition to reports submitted to CDRH nether the MDR regulation.

MEDICAL SUPERVISION

Physician substitutes (PSs) may perform most of the routine functions of a medico. Once the establishment has a Medico Substitute programme approved by CBER, it is non necessary for the institution to request approval for individual physician substitutes. The following documentation should be on the premises for each physician substitute: a curriculum vitae, current license or certificate in the land where practicing, electric current certification in cardiopulmonary resuscitation (CPR), documentation of training and physician evaluation and a signed statement of understanding. Investigators should review this documentation during inspections. Refer to CBER memorandum, "Physician Substitutes," dated August 15, 1988.

It is acceptable for a physician to be "constructively" on the premises, that is, able to make it on the premises within approximately fifteen minutes afterward existence contacted. Some Source Plasma establishments, however, accept a variance to provide physician intervention within 15 min past transporting the donor to a designated medical facility instead of the physician being "constructively bachelor". Source Plasma establishments should have procedures to provide ambulance service and emergency medical intendance, as well as explicit instructions regarding when and how to notify the physician and the md substitute. The telephone number of a specific emergency care facility and ambulance service should be posted and attainable to all employees, or a 911 system may be in effect in the area.

RBC IMMUNIZATIONS : Physicians are required [640.62] to be on the premises during immunizations, including RBC immunizations. A doctor substitute should be on the premises, in the absence of the physician, during immunizations with licensed vaccines.

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