GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS - Department 1

JUNE 1997
(APRIL 2001 - Editorial Revisions)

NOTE: This document is reference textile 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 whatever person(southward). An alternative arroyo may be used if such an approach satisfies the requirements of the applicable statues, regulations, or both.

Tabular array OF CONTENTS

SECTION 1
Introduction
Full general Information
Operations
Standard Operating Procedures
Errors, Accidents and Fatalities
Adverse Reaction
Lookback
Plasmapheresis Facilities
Equipment
Medical Device Reporting
Medical Supervision

SECTION 2
Donor Identification
Informed Consent
Initial Medical Examination
Immunization
Donor Suitability
Exceptional Donations
Blood Collection
Donor Record Files
Plasma Separation and Pooling (Manual Only)
Reinfusion of Blood-red Claret Cells (Manual Collection)

Department 3
HBsAg, Anti-HCV and Anti-HIV Testing
Handling of HBsAg, Anti-HCV and Anti-HIV Repeatedly Reactive Units
Serum Protein Quantitation
Serologic Examination for Syphilis
Storage
Distribution Record
Disposal of Infectious Waste
Computerized Records
Affliction State Donors
"High Risk" Donors
Source Leukocytes
Therapeutic Exchange Plasma

Department 1
INTRODUCTION

This guide, which provides the nigh updated interpretation of certain regulations and guidelines, was prepared by the FDA, Office of Regulatory Affairs (ORA) and the Eye for Biologics Evaluation and Research (CBER). This guidance represents the Agency'south electric current thinking regarding the inspection of source plasma establishments. It does non create nor confer any rights for or on any person and does non operate to bind FDA or the public. An alternative approach may be used by 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 Code of Federal Regulations, Title 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 two of the Compliance Policy Guides Manual.

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

The training of products for which in that location are no additional standards published in the Code of Federal Regulations (CFR) must be described in the establishment's standard operating procedures (SOP) manual and manufactured in accordance with the methods therein. Questions apropos the information independent in this guide should be addressed to CBER, Division of Inspections and Surveillance, Program Surveillance Branch (HFM-654) at 301-827-6220 , or the ORA/ORO Partition of Emergency and Investigational Operations at 301- 827-5653.

Full general INFORMATION

Investigators should asking to see the firm's blessing letter to manufacture Source Plasma, Source Leukocytes or Therapeutic Exchange Plasma and the letter that assigned a U.Southward. License Number to the firm. CBER assigns a license number after approval of the first biologic license application. 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 production label. The license number serves to identify establishments in correspondence, applications, and other forms of communication.

The investigator should besides review the establishment's validated re-create of Grade FDA-2830, Blood Establishment Registration and Production Listing, for the current calendar year or if evidence exists, that the firm submitted it to FDA. If the data on the registration form is not correct, study the corrections to exist made in the EIR, and instruct the institution to submit, in writing, the updated information to the CBER, Partitioning of Claret Applications, (HFM-370), 1401 Rockville Pike, Rockville, Dr. 20852-1448. Establishments should report changes in their name, accost or products to the Division of Blood Applications. They should submit these changes in a supplement to their biologic license. Establishments should notify CBER of changes in the Authorized Official by letter.

OPERATIONS

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

Decide from whom Source Plasma is beingness collected: normal donors, immunized donors, disease associated, disease state or high-chance donors. Donors may take pre-existing antibodies or may have been sensitized to produce specific antibody(due south) in an immunization program. Draw what disease states are applicable. Determine what products other than Source Plasma are beingness collected, for instance Source Leukocytes or Therapeutic Substitution Plasma. Source Plasma, Source Leukocytes and Therapeutic Exchange Plasma are is subject area 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 October 1997 the final rule on changes to an approved awarding became constructive. Changes may be fabricated in one of three categories based on the potential of the change to have an adverse effect on the identity, strength, quality, purity and authorization every bit they chronicle to the condom or effectiveness of the production. For further data 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 blessing letters should be available 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 affect the safety, purity, or dominance of the production, contact the Sectionalisation of Inspections and Surveillance (HFM-654) at 301-827-6220 .

STANDARD OPERATING PROCEDURES

A Source Plasma institution should submit a supplement to its biologic license application when making changes to the following SOPs: donor suitability, arm training for phlebotomy, AIDS educational data materials, donor history records, including informed consent forms, component preparation, and disposition of unsuitable products. The firm should have a machinery for maintaining SOPs, and the SOPs should exist readily available to the personnel performing the work in each area of manufacturing.

At that place should exist a written procedure to minimize the spread of infectious agents, and it should be consequent with electric current CDC and OSHA recommendations. OSHA published the final rule for the "Occupational Exposure to Bloodborne Pathogens" in the Dec six, 1991, Federal Annals. Included in the rule are requirements for facilities to develop procedures to ensure the safety 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 vesture as well every bit providing vaccination against Hepatitis B. Masks and face up or heart coverings or a shield may also exist used if the likelihood of exposure to infectious agents increases and represents a hazard. Investigators should hash out these issues with the firm at the shut of the inspection.

ERRORS, ACCIDENTS AND FATALITIES

Licensed establishments are required to report to the Director, Office of Compliance and Biologics Quality (OCBQ), CBER, all errors and accidents in manufacturing which may bear upon the prophylactic, purity, or potency of any product. CBER requires that this information be submitted through the Fault and Blow Reporting system. In the March 20, 1991, memorandum, "Responsibilities of Claret Establishments Related to Errors and Accidents in the Industry of Blood and Blood Components," unlicensed, registered establishments are requested to voluntarily report errors and accidents. Reports should be submitted promptly afterward errors and accidents are discovered. Errors or accidents that may affect the condom, purity, or potency of a production 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 mark tests;
  • units prior to completion of all tests;
  • incorrectly labeled components;
  • product incorrectly stored (due east.one thousand., incorrect storage/shipping temperature).

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

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

Special attention should be given to any collection-related fatality that occurred since the previous inspection. Fatalities are to be reported to CBER's Office of Compliance and Biologics Quality using 1 of the following options: (1) Telephone number 301-827-6220 ; (two) Email address "fatality@cber.fda.gov"; or (3) Fax number 301-827-6748 . In the event that an FDA investigator becomes enlightened of a previously unreported collection-related fatality, CBER's Division of Inspections and Surveillance (HFM-650) should be notified as shortly as possible at 301-827-6220 .

Agin REACTIONS

Every adverse reaction experienced past the donor, whether considered insignificant or severe, must be recorded by the firm. All donor adverse reactions must exist recorded in the donor'southward record; a separate adverse reaction file may besides be maintained by the firm. The adverse reaction should be satisfactorily documented by donor center personnel, including measures taken to aid the donor and the resolution of the reaction, and it should exist noted as having been evaluated by the licensed medico or physician substitute. Reactions, including but not limited to, lightheadedness, fainting, nausea, tingling, flushing, wheezing, chest hurting, low blood pressure, rapid middle rate, depression back hurting, bronchial spasms, difficulty breathing, loss of consciousness, and convulsions, should be evaluated past the physician/medico substitute. Reactions at the site of injection may include infection, itching, and hematoma. The Typhoon 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 observation, emergency transportation, or hospitalization, the donor record file (DRF) should include appropriate notation and medical approving by the md (not the doctor substitute) for the donor to continue participating in whatever program the donor is qualified. The procedure describing this evaluation should be in the SOP.

Incorrect red blood cell infusions and associated fatalities if any should exist documented by the firm and associated fatalities (if any) reported to CBER/Division of Inspections and Surveillance (HFM-650). Records relating to the incident must be maintained and made a function of each affected donor's tape. Complications of blood collection 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 Man Immunodeficiency Virus (HIV) Transmission by Blood and Blood Products" for additional guidance. Also see the FDA final rule, Current Good Manufacturing Practices for Claret and Blood Components: Notification of Consignees Receiving Blood and Blood Components at Increased Hazard for Transmitting HIV Infection, constructive November 8, 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 Homo T-Lymphotropic Virus Type I (HTLV-I)" dated July 19, 1996.

Refer to CBER's guidance for industry titled "Current Good Manufacturing Do for Blood and Blood 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); (2) Supplemental Testing, and the Notification of Consignees and Blood Recipients of donor Test Results for Anti-HCV, " dated September 1998, or the almost current guidance document.

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 gratuitous from insects/vermin. Hand washing facilities for personnel should be conveniently located; soap, towels, and hot water should exist available. If the sink is non in the same room equally the donor collection area, it should be in the immediate vicinity. Bathroom facilities should be close enough that donors and personnel may easily accomplish them.

In facilities that include laboratories for testing for infectious agents, a split up room for laboratory procedures is recommended. Nonetheless, a specific expanse designated for infectious amanuensis testing that is conspicuously labeled every bit such, is adequate. Testing laboratories should observe recommendations equally published in the Centers for Illness 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 Section of Health and Human Services (DHHS). It is publication No. (CDC) 88-8395, 94-95, 2nd Edition, Washington D.C.: U.S. Government Printing Function, 1988.

EQUIPMENT

During the form of an inspection, the investigator may find or review instances where equipment or supplies are misused or not performance as designed. Donor, operator, or production safety may be compromised when equipment is misused or SOPs and/or manufacturer instructions are not followed. It is important, therefore, that the firm's equipment and supplies be inspected, stored, maintained, calibrated, and used according to the manufacturer's supplied instructions. All equipment should perform in the style for which information technology was designed and intended for apply. A record relating to problems attributed to equipment and defective soft goods should be kept. Refer to the Source Plasma Compliance Plan 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 Found of Standards and Technology (NIST), prior to initial use, after repairs, when appropriate, and on a regularly scheduled ground as prescribed in the SOPs, the manufacturer'due south specifications and the regulations. Records of such activities shall be maintained.

The standardization and calibration of the microhematocrit centrifuge may be done with a commercially prepared command or by other methods, e.g., duplicate samples tested at multiple intervals. Use of capillary tubes, even so, should follow manufacturer'south instructions. The timer should be checked every iii months.

Scales : Procedures should include performance checks of all scales used in blood drove, i.e., trip scales and platform scales. Calibration should be washed as necessary, with appropriate records maintained. Regular quality command procedures for each automatic collection 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 "zero" point. Certain manufacturer's instructions may specify that a suitable protein-based command with a refractometer reading of 6-8 gm/dl exist used as a quality command check. Records must be maintained for daily standardization and for calibration in the upshot that the expected readings are non obtained. Serum or plasma is a sticky substance, and the surface of the refractometer should exist cleaned immediately afterward each use with distilled H2o. An aqueous disinfectant (1:100 bleach to water) may exist used to disinfect the surface of the refractometer one time the plasma is removed. If the prism of the refractometer is wiped only with dry material, it becomes scratched and may affect its suitability for utilize. Alcohol should non be used since information technology precipitates plasma protein and leaves a remainder.

Refractometer results should be able to be clearly read. Care should exist taken to allow 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 outcome in a "fuzzy" or "blurred" reading. A value for protein concentration is obtained by looking through the eyepiece and noting where the sharp boundary between dark and light fields crosses the appropriate scale (gm/dl). Sharp dissimilarity can only be 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 clinch that the times and temperatures beingness recorded are adequate for sterilization. Procedures should provide for scheduled calibration as necessary, including before initial use and after repairs. Calibration procedures should provide assurance that the autoclave functions as intended, i.due east., sterilization of arm preparation supplies and/or decontamination of biohazardous fabric.

Biological indicators should be used periodically and temperature indicators, such as heat sensitive record, should be used with each run to verify that the materials are beingness sterilized. A minimum of 121.5° C (251° F) for 60 minutes by saturated steam at a pressure of xv atmospheres is recommended for materials contaminated with claret; 20 minutes at the same temperature is recommended for arm training supplies.

Electronic Devices for Obtaining Vital Signs : When electronic devices (due east.g., IVAC) are used for blood force per unit area, pulse, and temperature determinations, the house should develop a quality control procedure to assure the device is operation properly. The operation bank check of the device should be done periodically and should non exist limited but to the electronic check for the temperature function. In addition to functioning checks, the blood force per unit area device should be calibrated, and the thermometer function should be checked for accuracy.

Collection Containers : Only FDA-approved blood collection containers (with proper amount of anticoagulant) should be used. Currently canonical blood collection containers with anticoagulant (except heparin) for transmission apheresis are manufactured by Baxter, Medsep, and Terumo. For more than recent approvals, contact the Division of Blood Applications (HFM- 370), 301-827-3524 . Blood collection containers shall exist checked for defects prior to utilize, and a method must be in place to chronicle the collection container to a donor.

But FDA-approved assistants/transfer sets and plasma containers should be in utilize.

Separated red claret cells may exist diluted and resuspended only in 0.85% to 0.9% Sodium Chloride Injection, USP, which tin can besides be used to keep the intravenous line and needle free from clots.

The nigh frequently used anticoagulant for transmission and automatic 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 crave CBER blessing of a license or license supplement.

Automatic APHERESIS EQUIPMENT - In a review of license applications, CBER considers an operator to device ratio of i:six for trained staff and 1:4 during grooming as acceptable. The ratio at tiffin and break periods should not differ from other times. However, 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 dorsum-upwards in the outcome 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 exist a part of the establishment's SOP. Refer to CBER memorandum titled, "Book 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 training program should include troubleshooting and problem-solving of mutual problems that occur with the device. Once basic training has been completed and documented, a plan for periodic updating and reassessment of operator skills, with appropriate documentation, should exist in identify.

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 twenty-four hours of employ: all alert letters received by type; all disposable equipment failures (due east.g., leakage and breakage); instrument failures (e.yard., electronics); all donor reactions, regardless of perceived significance; and whatsoever other problems noted. The maintenance and repair records of each separate automated collection device in use may provide testify of problems or failures and cosmetic deportment taken.

Daily set-upward of the device shall include a weight scale check using a known weight. Before the device is initially placed into use and later repairs, there should be documentation of satisfactory performance of the device. In that location should be a record of performance checks, the results of whatsoever problems discovered, and the identity of the operator performing the checks. Bug should be satisfactorily resolved every bit evidenced by documented review. A program of periodic preventive maintenance must too be written and followed by the establishment. Preventive maintenance plans are more often than not written by the manufacturer of the plasmapheresis equipment.

There should be a system to ensure that the maximum time for saline assistants and/or anticoagulant set does non exceed four hours. There is a adventure of bacterial contamination once the purse of saline or anticoagulant is entered to connect the solutions to the apheresis set. 4 hours is considered the maximum time menses that these solutions should be connected prior to product donor collection.

MEDICAL DEVICE REPORTING (MDR)

A Source Plasma manufacturer who likewise articles a medical device is subject to the Medical Device Reporting (MDR) regulations, 21 CFR 803. The MDR regulations crave that manufacturers of medical devices and certain types of medical institutions study any death or serious injury that a medical device may have caused or which was identified as being a contributing factor to the death. Device manufacturers are also required to report device malfunctions that are likely to cause or contribute to a death or serious injury if they were to recur. Device manufacturers and user facilities are required to constitute and maintain written MDR procedures and MDR effect files consequent with 21 CFR 803.17 and 803.eighteen respectively. Device manufacturers should report all reportable deaths, serious injuries and malfunctions to FDA within the time menstruum specified in the MDR regulations.

Medical institutions, such equally hospitals, nursing homes, ambulatory surgical facilities, and outpatient diagnostic or treatment facilities are referred to every bit user facilities and are too subject field 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 i of its patients if an automated collection device used by the Source Plasma operation contributed to the expiry or serious injury.

Within ten days, user facilities must written report all deaths to FDA and to the device manufacturer, if known. Within ten days, they must also 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. Bug with a device e.g., 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 complexity of claret drove is confirmed to be fatal, the Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research must as well be notified in accord with 21 CFR 606.170(b). This requirement is in addition to reports submitted to CDRH nether the MDR regulation.

MEDICAL SUPERVISION

Doc substitutes (PSs) may perform almost of the routine functions of a physician. In one case the institution has a Physician Substitute program approved by CBER, information technology is not necessary for the institution to request blessing for private physician substitutes. The following documentation should exist on the premises for each physician substitute: a curriculum vitae, current license or certificate in the state where practicing, current certification in cardiopulmonary resuscitation (CPR), documentation of training and physician evaluation and a signed statement of agreement. Investigators should review this documentation during inspections. Refer to CBER memorandum, "Doctor Substitutes," dated August xv, 1988.

Information technology is acceptable for a doc to be "constructively" on the premises, that is, able to arrive on the premises inside approximately fifteen minutes after being contacted. Some Source Plasma establishments, however, have a variance to provide doctor intervention within 15 min by transporting the donor to a designated medical facility instead of the physician being "constructively available". Source Plasma establishments should have procedures to provide ambulance service and emergency medical care, as well every bit explicit instructions regarding when and how to notify the physician and the physician substitute. The telephone number of a specific emergency care facility and ambulance service should exist posted and accessible 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 medico substitute should exist on the premises, in the absenteeism of the dr., during immunizations with licensed vaccines.

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