GUIDE TO INSPECTIONS OF SOURCE PLASMA ESTABLISHMENTS - Incision 1

JUNE 1997
(APRIL 2001 - Editorial Revisions)

Banknote: This document is reference material 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 someone(s). An alternative approach may be victimized if such an approach satisfies the requirements of the applicable statues, regulations, or some.

TABLE OF Table of contents

SECTION 1
Introduction
General Information
Operations
Normal Operating Procedures
Errors, Accidents and Fatalities
Adverse Reaction
Lookback
Plasmapheresis Facilities
Equipment
Health chec Device Reporting
Medical Supervision

SECTION 2
Bestower Identification
Informed Accept
First Medical Examination
Immunization
Conferrer Suitability
Infrequent Donations
Blood Solicitation
Donor Record Files
Plasma Separation and Pooling (Manual Only)
Reinfusion of Red Blood Cells (Manual Collection)

SECTION 3
HBsAg, Anti-HCV and Anti-HIV Testing
Handling of HBsAg, Opposed-HCV and Opposed-HIV Repeatedly Reactive Units
Blood serum Protein Quantitation
Serologic Trial for Syphilis
Storage
Distribution Record
Disposal of Infectious Waste
Computerized Records
Disease State Donors
"High Take a chanc" Donors
Reference Leukocytes
Therapeutic Exchange Plasma

SECTION 1
Innovation

This guide, which provides the almost updated interpretation of certain regulations and guidelines, was prepared by the FDA, Office of Restrictive Personal matters (ORA) and the Center for Biologics Evaluation and Inquiry (CBER). This guidance represents the Agency's stream thinking regarding the inspection of source plasma establishments. It does not make over nor confer any rights for or connected any person and does not operate to bind FDA or the public. An alternative approach may be used by industry if much approach satisfies the requirements of the applicable statute, regulations, or both.

This guide is intended to beryllium in use in conjunction with the FDA/Investigations Operations Manual (IOM); the Code of Federal Regulations, Title 21 (21 CFR); the Deference Program for the Inspection of Source Plasm Establishments (CP 7342.002); and the Compliance Policy Guides (CPG) for Biologics, which are contained in Chapter 2 of the Compliance Policy Guides Manual.

Flow counsel documents and preceding blood memoranda published aside CBER whitethorn be available at the FDA District Offices or a copy bathroom be obtained through the CBER Facsimile machine Data System, 1-888-CBER-FAX , or past accessing the CBER home 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) mustiness be described in the governance's standard operating procedures (SOP) manual and manufactured in accordance with the methods therein. Questions concerning the information contained in this guide should be addressed to CBER, Variance of Inspections and Surveillance, Program Surveillance Fork (HFM-654) at 301-827-6220 , or the ORA/ORO Division of Emergency and Investigational Operations at 301- 827-5653.

Unspecialised INFORMATION

Investigators should request to hear the firm's approval letter to inven Source Plasm, Origin Leukocytes or Sanative Convert Plasma and the missive that appointed a U.S. Registration number to the firm. CBER assigns a license number after approval of the first biologic permit lotion. The approval letter identifies the products that may be delivered or introduced for bringing into interstate commerce and the registration number mustiness come along on the product label. The license number serves to identify establishments in correspondence, applications, and other forms of communication.

The researcher should also revaluation the ecesis's validated copy of Form FDA-2830, Parentage Establishment Adjustment and Product Listing, for the current civil year or if evidence exists, that the loyal submitted it to FDA. If the data along the adjustment form is non correct, report the corrections to be made in the EIR, and instruct the establishment to submit, in writing, the updated data to the CBER, Division of Blood Applications, (HFM-370), 1401 Rockville Motorway, Rockville, MD 20852-1448. Establishments should report changes in their name, address or products to the Division of Blood Applications. They should submit these changes in a supplement to their biologic certify. Establishments should notify CBER of changes in the Authorized Official away letter.

Trading operations

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

Determine from whom Source Plasma is beingness self-collected: modal donors, immunized donors, disease associated, disease commonwealth or high-risk donors. Donors May have preceding antibodies or may undergo been sensitized to produce precise antibody(s) in an immunization program. Describe what disease states are applicable. Determine what products other than Source Plasma are being collected, for case Source Leukocytes surgery Therapeutic Exchange Plasma. Source Plasm, Source Leukocytes and Therapeutic Exchange Plasma are is theme to the licensure provisions of Section 351 of the Public Health Service Act and may only be shipped in interstate commerce if the Source Plasma producer has an unsuspended and unrevoked U.S. License.

In October 1997 the net rule on changes to an approved application became effective. Changes may be made in one of deuce-ac categories based on the potential of the change to have an adverse outcome on the identity, strength, quality, purity and potency as they relate to the condom or effectuality of the product. For encourage selective information regarding reporting changes come to to 21 CFR 601.12, and the CP7342.001 - Inspection of Licensed and Unlicensed Blood Banks, Brokers, Reference Laboratories, and Contractors.

Not all procedures are reviewed and approved by CBER. CBER approval letters should be available for review during the inspection. CBER does not follow-up and sanction all procedures, thence, if an investigator observes a procedure that is well-advised unsafe for the donor or that may strike the condom, purity, or say-so of the product, inter-group communication the Air division of Inspections and Surveillance (HFM-654) at 301-827-6220 .

STANDARD In operation PROCEDURES

A Source Plasma establishment should subject a supplement to its biologic license application when fashioning changes to the following SOPs: conferrer suitability, arm preparation for phlebotomy, AIDS educational information materials, donor account records, including conversant consent forms, element preparation, and disposition of unsuitable products. The firm should have a mechanism for maintaining SOPs, and the SOPs should be readily available to the staff office performing the play in each area of manufacturing.

At that place should be a written subroutine to minimize the spread of infectious agents, and it should be consistent with current Center for Disease Control and Prevention and OSHA recommendations. OSHA published the final rule for the "Occupational Exposure to Bloodborne Pathogens" in the December 6, 1991, Northern Register. 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 habitually may follow followed admit wearing gloves and protective clothing as well as providing vaccination against Hepatitis B. Masks and face or eye coverings or a shield may also follow used if the likelihood of exposure to infectious agents increases and represents a hazard. Investigators should discuss these issues with the firm at the close of the inspection.

ERRORS, ACCIDENTS AND FATALITIES

Commissioned establishments are required to report to the Manager, Office of Compliance and Biologics Quality (OCBQ), CBER, all errors and accidents in manufacturing which may affect the safety, whiteness, or potency of any product. CBER requires that this entropy be submitted through the Misplay and Accident Reporting system. In the March 20, 1991, memorandum, "Responsibilities of Blood Establishments Related to Errors and Accidents in the Manufacture of Blood and Blood Components," unaccredited, registered establishments are requested to voluntarily report errors and accidents. Reports should be submitted promptly after errors and accidents are determined. Errors or accidents that may regard the safety, purity, or potency of a product admit, but are not limited to, the release of the following:

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

Establishments that perform their own testing or shorten KO'd examination should report errors and accidents to CBER. Contract examination laboratories should promptly notify client establishments of errors in testing so that plasm establishments may take appropriate action on encyclical products readily. The guest plasma establishment should ascertain if an error/chance event report to CBER is necessary and/OR if recovery of cartesian product is necessary.

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

Special tending should be given to any collection-related human death that occurred since the previous review. Fatalities are to be reported to CBER's Billet of Compliancy and Biologics Quality victimisation unitary of the following options: (1) Telephony number 301-827-6220 ; (2) E-mail address "human death@cber.fda.gov"; Oregon (3) Fax list 301-827-6748 . In the event that an FDA investigator becomes aware of a previously unreported collection-related fatality, CBER's Division of Inspections and Surveillance (HFM-650) should be notified as soon A possible at 301-827-6220 .

ADVERSE REACTIONS

Every adverse chemical reaction experienced past the presenter, whether thoughtful insignificant or severe, must be recorded by the unwaveringly. All donor unfavourable reactions must be canned in the donor's record; a unintegrated adverse reaction file Crataegus oxycantha also be maintained by the firm. The adverse response should be satisfactorily documented by donor center personnel, including measures taken to assist the donor and the resolution of the reaction, and it should be noticeable as having been evaluated by the licensed physician surgery physician substitute. Reactions, including but not limited to, lightheadedness, fainting, nausea, tingling, flushing, unhealthy, chest pain, low blood pressure, speedy heart grade, low rearmost pain, bronchial spasms, difficulty breathing, loss of cognisance, and convulsions, should be evaluated by the physician/physician substitute. Reactions at the site of injectant may admit infection, itching, and hematoma. The Draft Reviewers' Point "Informed Go for for Plasmapheresis/Immunization" provides additive information on possible reactions. Follow-up book of instructions regarding donor care should also be added to the documentation of the chemical reaction. In those cases where a donor has mandatory extended observation, exigency transportation, or hospitalization insurance, the donor record file (DRF) should include appropriate notation and medical approval by the medic (not the physician unreal) for the donor to continue participating in any program the donor is qualified. The procedure describing this evaluation should be in the SOP.

Wrong red blood cell infusions and joint fatalities if any should be documented by the firm and associated fatalities (if any) reported to CBER/Class of Inspections and Surveillance (HFM-650). Records relating to the incident mustiness be maintained and made a part of to each one affected donor's record. Complications of blood collection that result in a fatality are the just donor reactions that Source Plasm establishments are necessary to report card to CBER. The SOP should computer address procedures for documenting the human death and required reporting.

LOOKBACK Insurance

Pertain to the April 23, 1992, memorandum "Revised Recommendations for the Prevention of HIV (HIV) Infection by Blood and Blood Products" for additive guidance. Also run into the FDA final rule, Current Ample Manufacturing Practices for Blood and Blood Components: Presentment of Consignees Receiving Blood and Rip Components at Increased Risk for Transmitting Human immunodeficiency virus Infection, effective November 8, 1996. For Hepatitis see "Recommendation for the Quarantine and Temperament 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 Case I (HTLV-I)" dateable July 19, 1996.

Cite to CBER's guidance for industry titled "Current Solid Manufacturing Exercise for Blood and Blood Components: (1) Quarantine and Tendency of Units from Prior Collections from Donors with Repeatedly Reactive Showing Tests for Antibody to Hepatitis C Computer virus (Anti-HCV); (2) Supplemental Testing, and the Notification of Consignees and Blood Recipients of bestower Test Results for Opposing-HCV, " dated September 1998, or the nigh current guidance document.

PLASMAPHERESIS FACILITIES

All suite and work areas where manufacturing operations are performed must meet CGMP regulations, including order, cleanliness, lack of clutter, good inflammation and ventilation, and are footloose from insects/vermin. Hand laundry facilities for personnel should be conveniently located; soap, towels, and hot water should be available. If the sink is not in the same room as the donor collection area, it should be in the proximate vicinity. John facilities should be close sufficiency that donors and personnel whitethorn easily reach them.

In facilities that admit laboratories for testing for infectious agents, a separate elbow room for laboratory procedures is recommended. However, a specific area designated for contaminating agentive role testing that is clearly labeled per se, is good. Testing laboratories should observe recommendations as publicized in the Centers for Disease Control and Prevention (CDCP) and the NIH (NIH) publication entitled "Biosafety in Microbiological and Biomedical Laboratories." The publication is available direct the Department of Wellness and Human Services (DHHS). It is publication No. (CDC) 88-8395, 94-95, 2nd Edition, American capital D.C.: U.S. Government Printing Post, 1988.

EQUIPMENT

During the trend of an review, the investigator may respect operating theater review instances where equipment or supplies are misused or non operative as designed. Donor, hustler, or intersection safety may be compromised when equipment is misused or Sop and/or manufacturer instructions are not followed. It is important, therefore, that the immobile's equipment and supplies be inspected, stored, maintained, graduated, and used according to the producer's supplied instructions. All equipment should perform in the personal manner for which it was designed and intended for use. A record relating to problems attributed to equipment and defective muffled goods should live unbroken. Refer to the Source Plasm Conformity 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 identified standards, i.e. National Found of Standards and Technology (NIST), prior to initial use, after repairs, when appropriate, and on a on a regular basis scheduled basis as prescribed in the SOPs, the manufacturer's 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 preconditioned verify or by other methods, e.g., replicate samples tested at multiple intervals. Enjoyment of thin tubes, however, should stick with manufacturer's instructions. The timer should be checked every three months.

Scales : Procedures should let in performance checks of all scales used in blood compendium, i.e., actuate scales and political program scales. Calibration should Be done as necessary, with appropriate records maintained. Usual quality control condition procedures for each automated collection gimmick should include checking the graduated table with external standard weights to verify accuracy of the electronic scale.

Refractometer : Distilled water should be used to standardize the refractometer to the "naught" point. Sealed manufacturer's instructions may specify that a suitable protein-based control with a refractometer indication of 6-8 gm/dl be used as a quality control check. Records must beryllium maintained for daily calibration and for standardization in the event that the expected readings are not obtained. Serum or plasma is a gummy substance, and the come on of the refractometer should beryllium cleaned now after from each one use with distilled H2O. An binary compound disinfectant (1:100 discoloris to water) may atomic number 4 used to disinfect the surface of the refractometer once the plasma is removed. If the prism of the refractometer is wiped solely with dry material, it becomes scraped and may affect its suitability for employment. Alcohol should non live used since it precipitates plasma protein and leaves a remainder.

Refractometer results should be able to glucinium clearly read. Concern should be taken to allow the serum or plasma to feed over the optical prism, rather than moving the capillary directly along the optical prism. Extensive scratching of the refractometer prism may result in a "fuzzy" operating theatre "blurred" reading. A prise for protein compactness is obtained by looking direct the eyepiece and noting where the sharp boundary between dark and light fields crosses the appropriate scale (gm/dl). Cutting line can only be verified by looking into the refractometer. The manufacturing business's instructions for payload taste and reading results should be followed.

Autoclave : Periodic performance checks are necessary to promise that the multiplication and temperatures being recorded are adequate for sterilization. Procedures should supply for scheduled standardization as needful, including in front first manipulation and after repairs. Calibration procedures should provide assurance that the steriliser functions as intended, i.e., sterilization of arm homework supplies and/or decontamination of biohazardous incarnate.

Biological indicators should be victimized periodically and temperature indicators, such as hot up sensitive tape, should be used with each run to verify that the materials are being germfree. A minimum of 121.5° C (251° F) for 60 minutes by saturated steam at a pressure of 15 atmospheres is suggested for materials contaminated with blood; 20 minutes at the same temperature is recommended for arm preparation supplies.

Electronic Devices for Obtaining Vital Signs : When physical science devices (e.g., IVAC) are used for blood pressure, pulse, and temperature determinations, the unwaveringly should develop a quality ascendancy operation to assure the device is functioning properly. The performance suss out of the device should be done sporadically and should not be finite only to the physical science check for the temperature function. In addition to performance checks, the blood pressure device should be calibrated, and the thermometer function should Be checked for accuracy.

Assemblage Containers : Only FDA-approved blood collection containers (with proper amount of anticoagulant medication) should be used. Currently approved blood collection containers with anticoagulant (except heparin) for manual of arms apheresis are manufactured aside Baxter, Medsep, and Terumo. For more recent approvals, contact the Division of Blood Applications (HFM- 370), 301-827-3524 . Roue collection containers shall glucinium checked for defects prior to use, and a method must represent in place to relate the collection container to a conferrer.

Only FDA-approved administration/conveyance sets and plasma containers should be in employment.

Separated red ancestry cells may constitute weakened and resuspended simply in 0.85% to 0.9% Common salt Injection, USP, which can also be victimized to prevent the intravenous line and needle free from clots.

The most frequently in use anticoagulant medication for manual and automatic pheresis is 4% Sodium Citrate. Other commonly utilised anticoagulants are citrate dextrose solution (ACD) and citrate phosphate dextrose (CPD). Collection in strange anticoagulants or changes in formulation from that in 21 CFR 640.64 need CBER favourable reception of a license or license supplement.

AUTOMATED APHERESIS EQUIPMENT - In a review of license applications, CBER considers an operator to device ratio of 1:6 for trained staff and 1:4 during training Eastern Samoa unobjectionable. The ratio at lunch and break periods should non dissent from other multiplication. However, investigators should evaluate the competency of the staff and whether they are adequate in number. In addition CBER recommends that a fully housebroken operator be available as a back-dormy in the event problems arise.

The amount of plasma to be collected is device-specific and based along the device manufacturer's approved nomograph or the FDA abbreviated nomogram, either of which must also represent a set forth of the establishment's Souse. Mention to CBER memorandum titled, "Bulk Limits for Automated Collection of Source Plasma," dated November 4, 1992.

Operator training is essential in ensuring the appropriate and safe use of automated plasmapheresis devices. The content of the breeding political program should include troubleshooting and problem-solving of common problems that occur with the twist. Once basic preparation has been consummated and documented, a platform for rhythmic updating and reassessment of operator skills, with appropriate documentation, should comprise in direct.

A log for each device essential be maintained and moldiness (606.160) include the identicalness of the operator when the device is used. The device log should include the following for from each one sidereal day of use of goods and services: all alarm messages acceptable by type; all usable equipment failures (e.g., leakage and breakage); instrument failures (e.g., electronics); all donor reactions, disregardless of sensed significance; and any other problems noted. The maintenance and repair records of each separate automated collection device busy may provide grounds of problems or failures and corrective actions taken.

Daily set-up of the device shall include a weight scale check using a known weight. Before the twist is initially placed into habituate and after repairs, there should be documentation of satisfactory performance of the device. There should be a record of performance checks, the results of whatsoever problems discovered, and the identity of the operator performing the checks. Problems should be satisfactorily resolved as evidenced by documented review. A computer programme of periodic preventive maintenance must also atomic number 4 written and followed away the establishment. Preventive upkeep plans are generally written by the manufacturer of the plasmapheresis equipment.

On that point should beryllium a system to ensure that the maximum time for saline administration and/or anticoagulant lay out up does non exceed four hours. Thither is a risk of bacterial pollution once the bag of saline or anticoagulant is entered to connect the solutions to the pheresis congeal. Quatern hours is considered the utmost time historical 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 gimmick is subjugate 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 some death operating theatre serious injury that a medical device may have caused or which was identified as beingness a conducive factor to the death. Device manufacturers are also required to reputation device malfunctions that are likely to cause OR contribute to a end or serious injury if they were to go back. Device manufacturers and user facilities are required to establish and maintain written MDR procedures and MDR event files consistent with 21 CFR 803.17 and 803.18 respectively. Device manufacturers should report all reported deaths, serious injuries and malfunctions to FDA within the time stop nominal in the MDR regulations.

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

Within ten days, user facilities must report entirely deaths to FDA and to the device manufacturer, if known. Inside ten days, they must also report a serious injury to the gimmick manufacturer or if the device manufacturer is not known, to FDA. User facilities should report complaints connected the identity, quality, durability, reliability, base hit, effectiveness or operation of a device to the device manufacturer. Problems with a twist e.g., a product defect or malfunction may also be reported direct to the FDA.

Connected a semiannual basis, user facilities must put in to FDA a summary of entirely MDR reports submitted to Food and Drug Administration and/or gimmick manufacturers during the reporting period (21 CFR 803.33).

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

MEDICAL SUPERVISION

Physician substitutes (PSs) may perform most of the routine functions of a physician. Once the establishment has a Doc Substitute program approved by CBER, IT is non necessary for the constitution to request favourable reception for idiosyncratic physician substitutes. The following documentation should be on the premises for each doctor sub: a CV, current permit or certificate in the submit where practicing, current documentation in cardiopulmonary resuscitation (Cardiac resuscitation), documentation of training and physician evaluation and a signed statement of understanding. Investigators should review this documentation during inspections. Refer to CBER memoranda, "Physician Substitutes," unstylish Venerable 15, 1988.

It is received for a physician to be "constructively" on the premises, that is, able to arrive on the premises inside approximately 15 minutes afterward being contacted. Some Rootage Plasma establishments, however, let a variance to provide physician intervention within 15 min by transporting the donor to a designated medical facility instead of the physician being "constructively for sale". Source Plasma establishments should have procedures to provide ambulance service and emergency medical care, as well as express instructions regarding when and how to notify the physician and the physician substitute. The telephone number of a particularized emergency care facility and ambulance service should be posted and accessible to all employees, Beaver State a 911 system English hawthorn be operative in the area.

Erythrocyte IMMUNIZATIONS : Physicians are required [640.62] to atomic number 4 connected the premises during immunizations, including RBC immunizations. A physician step in should get on the premises, in the petit mal epilepsy of the Dr., during immunizations with authorized vaccines.

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