CHAPTER 2 - BIOLOGICS

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CONTENTS

Sub Chapter 200 - 220:  General

205.100     Standards and Minimum Requirements for Biologic Products
210.100     Licensing - Changes to be Reported to the Office of Biologics
210.150     Importation of Licensed Biologic Products for Human Use
215.100     IND Filings; Completion of Applicable Portions Prior to Final 
Action on License Applications or License Amendments
220.100     Interstate Shipment of Biological Products for Use in Medical  
Emergencies

Sub Chapter 230:   Blood

230.100     Blood and Blood Products - Definitions  
230.110     Registration of Blood Banks and Others Firms Collecting,   
Manufacturing, Preparing or Processing Human Blood or 
Blood Products
230.120     Human Blood and Blood Products as Drugs   
230.130     Adequate Space for Determination of Donor Suitability  

Sub Chapter 231:   Platelets

231.100     Platelets, Pooled 
231.110     Quality Control Testing of Platelet Concentrate (Human)     
and Cryoprecipitated Antihemophilic Factor (Human)
231.120     Time Period for Separation of Platelets from Platelet-Rich 
Plasma When Preparing Platelets and Fresh Frozen Plasma
231.130     Storage of Platelet Concentrate (Human) for up to Five Days

Sub Chapter 250 - 256: Plasma

250.100     Source Plasma - Guidelines for Informed Consent Forms
250.500     Plasma Brokers - Registration and Compliance with Good 
Manufacturing Practices
251.100     Schedule of Physical Examination for Donors Receiving 
Immunization Injections
252.100     Source Plasma - Regulatory Action Based on Overbleeding 
253.100     Use of Units of Plasma and Fresh Frozen Plasma Which Have 
Been Thawed
254.100     Source Plasma - Use of Units from Donors Subsequently
Found to be Reactive to a Serologic Test for Syphilis
255.100     Quantitative Testing for Serum Proteins in Plasmapheresis 
Donors
256.100     Plasmapheresis - 48-hour Period Between Plasmapheresis
Procedures



Sub Chapter 270 - 275: Non-blood Products

270.100     Final Container Labels - Allergenic Extracts Containing 
Glycerin; Reporting Changes
275.100     Immune Milk 

__________________________________________

Sub Chapter 200 - 220 General

Sec. 205.100 Standards and Minimum Requirements for Biologic Products (CPG 7134.03)

BACKGROUND:

The Title 21 of the Code of Federal Regulations, Subchapter F, Part 600 to 680 contains the Regulations for the manufacture of biologic products and the Additional Standards for biologics requiring U.S. licensure.

Additional Standards have been published for the following bacterial, viral, blood, diagnostic and miscellaneous biologics:

Minimum Requirements remain in effect for biologic preparations for which standards have not been published as follows:

There are a number of biologic products for which Minimum Requirements are no longer in effect because the manufacture of the products has been discontinued by licensed manufacturers of the products concerned, or, as in the case of Yellow Fever Vaccine, the World Health Organization Standards are now used in lieu of Minimum Requirements.

POLICY:

Present *Center for Biologics Evaluation and Research* policy is to prepare Additional Standards rather than Minimum Requirements for biologic products since Minimum Requirements have not been kept current. In those instances where there is an inconsistency between a provision in the Minimum Requirements with a provision in the Regulations contained in 21 CFR, Part 600 to 680, the Regulations take precedence.

*Material between asterisks is new or revised*

[] Indicates material has been deleted

Issued: 7/15/74
Revised: 10/5/79, 10/1/80, 3/95

Sec. 210.100 Licensing - Changes to be Reported to the *Director, Center for Biologics Evaluation and Research* - 21 CFR 601.12 (CPG 7134.05)

BACKGROUND AND POLICY:

All licensed manufacturers are aware that important proposed changes in location, equipment, management and responsible personnel or in manufacturing methods and labeling of any product shall be reported to the Director, *Center for Biologics Evaluation and Research (CBER),* by the manufacturer, 30 days in advance of the time such changes are intended to be made, unless in case of emergency. Failure to report a change may *constitute* grounds for suspension and/or revocation of a license.

Reporting of a change in the Responsible Head or in managerial-level positions should be accompanied by a curriculum vitae of the individual nominated for the position and a statement *of understanding* from the nominee that he/she has read and is familiar with applicable sections of *Title 21, Code of Federal* Regulations relating to the manufacture of biologic products. A change in the Responsible Head shall not be instituted until the manufacturer has received notification of acceptance of the change.

Similarly, reporting a change in the location of the licensed manufacturing facility must be accompanied by an amended establishment license application *and product license apllication (PLA) amendment if process changes occur*, signed and dated by the Responsible Head, and a detailed floor plan of the new manufacturing facility. Biologics manufactured or prepared at the new location shall not be distributed under license until the manufacturer has received notification of acceptance of the location *(and amended PLA, if applicable)*.

In accordance with 21 CFR 601.12*(b) important* proposed changes in manufacturing methods and labeling also may not become effective until notification of acceptance is received from *CBER*.

*Material between asterisks is new or revised*

Issued: 7/19/76
Revised: 10/1/80, 3/95

Sec. 210.150 Importation of Licensed *Biological* Products for Human Use (CPG 7134.09)

BACKGROUND:

*Prior to 1974,* permits *were issued* for the importation of all *licensable biological* products and biologic materials subject to the short supply provisions of the regulations *(21 CFR 601.22).* In July 1974, *biological products* became subject to a dual import clearance process when FDA began processing entries of all regulated commodities through the use of the FD-700 set which is completed by the broker or importer of record, and submitted to the FDA District Office with jurisdiction over the port of entry.

Manufacturer's Memorandum of May 24, 1976, eliminated this duplication of effort by notifying all licensed manufacturers, who ship or import licensed *biological* products of the discontinuance of permit issuances.

NOTE: *Biological* products for veterinary use are subject to U.S.D.A. jurisdiction; no FDA permit or FD-700 set is required for their importation.

POLICY:

Materials subject to regulation as biologics should be cleared by use of the FD-700 set by the FDA District Office with jurisdiction over the port of entry.

The *Center for Biologics Evaluation and Research (CBER)* will consider the provisions of 21 CFR 601.31, (requirement for filing with the *CBER* the name and address of each consignee) to have been fulfilled, if a copy of the completed FD-701 is sent by the licensed foreign establishment or its agent to *CBER.*

*Material between asterisks is new or revised*

Issued: 7/28/76
Revised: 12/16/76, 10/1/80, 3/95

Sec. 215.100 IND Filings; Completion of Applicable Portions Prior to Final Action on License Applications or License *Supplements* (CPG 7134.07)

BACKGROUND AND POLICY:

No final action will be taken by the *Center for Biologics Evaluation and Research* on license applications or license *supplements* that involve clinical studies conducted under an IND filing until final reports for all applicable clinical studies have been received and reviewed by the *appropriate division within the Office of Blood Research and Review, Office of Vaccine Research and Review, or Office of Therapeutics Research and Review* and found to be complete and satisfactory. These IND submissions should include detailed summary reports for each clinical investigator as well as the sponsor's detinical summary and evaluation of the safety and efficacy of the product. A description of the final disposition of the *remaining lots of the* experimental drug should also be provided.

In order to prevent unnecessary delays, it is recommended that this information be submitted under the IND filing at the same time the final clinical data *report* is submitted under the pertinent pending license application or license *supplement.*

*Material between asterisks is new or revised*

Issued: 7/19/76
Revised: 10/1/80, 3/95

Sec. 220.100 Interstate Shipment of *Biological* Products for Use in Medical Emergencies (CPG 7134.11)

BACKGROUND:

*The interstate shipment for* sale, barter or exchange of any *biological* product [] is prohibited unless it has been manufactured at an establishment which holds an unsuspended and unrevoked license, pursuant to Section 351 of the Public Health *Service* Act.

Occasionally, when a medical emergency arises, an establishment may be requested to ship an unlicensed *biological* product interstate.

POLICY:

Unscheduled and infrequent interstate shipments of *biologicals products,* not intended for sale, barter, or exchange, for use in medical emergencies, for which documentation is maintained and made available for Agency examination, do not *ordinarily* constitute the types of transactions which would require licensure.

The Agency *reserves* the right to review the documentation relating to such incidents on an individual basis, to prevent the shipment of unlicensed products under the guise of responding to a medical emergency. Such documentation must be maintained at the establishment which ships the product in response to the emergency.

If, after thorough review of all documentation and other pertinent information, the Agency determines that the incident was an attempt to circumvent the regulations, regulatory action *should* be considered.

*Material between asterisks is new or revised*

[] Indicates material has been deleted

Issued: 12/1/77 as 7134.12
Revised: 10/1/80, 3/95

Sub Chapter 230 Blood

Sec. 230.100 Blood and Blood Products - Definitions (CPG 7134.12)

BACKGROUND:

Out of necessity, the Center for *Biologics Evaluation and Research (CBER) and the industry have established terminology used to designate specific blood products. Although these products may be mentioned in the regulations, they often are not fully defined. The intent of this guide is to define and clarify that terminology about which confusion has been expressed.

POLICY:

Recovered [] Plasma

Recovered [] Plasma is derived from single units of Whole Blood, or * * Plasma, or as a by-product in the preparation of blood components from whole blood collection. It is an unlicensed raw material intended for use in the manufacture of both licensed and unlicensed products, such as licensed fractionation products for injection, licensed diagnostic products; and diagnostic products not subject to license, including clinical chemistry controls. A license is not required to manufacture, distribute, relabel, pool, or repack Recovered [] Plasma.

When Recovered [] Plasma is to be used in licensed products, it must be shipped in full compliance with the provisions of 21 CFR 601.22 (Short Supply) by the short supplier (the initial manufacturer) or an authorized agent (the licensed manufacturer's agent) solely to the manufacturer under whose license the short supplier or an authorized agent is on file. Recovered [] Plasma for use in manufacturing licensed products may be pooled by the short supplier if complete records, including donor numbers for each unit pooled, are maintained. Any product manipulated by an authorized agent cannot be shipped under the short supply provisions.

Recovered [] Plasma pooled by other than the short supplier or manufacturer may be sold for use only in manufacturing unlicensed products, including clinical chemistry controls, and must be labeled, inter alia, "Not for use in products subject to license under Section 351 of the Public Health Service Act".

All firms that manufacture, relabel, pool, or repack recovered human plasma are required to register and follow appropriate GMP's for blood and blood products. Dealers who act only as authorized agents and do not take physical custody of the product are exempted from the registration requirements.

Salvaged [] Plasma

Salvaged [] Plasma is the name give to plasma originally collected as Source Plasma [], but because of: 1) its exposure to storage temperatures in excess of 10^o C; or 2) its collection during a period of noncompliance (usually, material in inventory at the time of license suspension due to deviations which occurred during the manufacturing of those units, and which affect or may affect the safety, purity, or potency of the plasma,) is not permitted to be used as a licensed product. It is restricted to use in the manufacture of products not subject to license under Section 351 of the Public Health Service Act.

Short Supply

The concept of "Short Supply" as it pertains to blood products recognizes that: 1) there are only a limited number of persons who can serve as donors of blood which contains high concentrations of antibodies needed for the preparation of special blood typing serums and immune globulins; and 2) Recovered [] Plasma is a valuable resource for fractionation products. In order to have access to these source materials throughout the country, licensed manufacturers are permitted to use other persons or firms, not a part of their own establishment, to collect blood and plasma and to perform the initial and partial manufacturing steps required to prepare these intermediate products for shipment to the licensed manufacturer.

To utilize the short supply provisions (21 CFR 601.22), the manufacturer holding a license to prepare the finished biological product must establish with his suppliers, those procedures, inspections, tests or other arrangements necessary to assure full compliance with the applicable regulations. A list of suppliers with whom the licensed manufacturer has a short supply agreement must be on file at the *CBER*. No products can be obtained under short supply until proper agreements have been entered into by the licensed manufacturer of the final product and the person or firm actually collecting the source material. No source material collected prior to the completion of such agreements, or subsequent to their terminations, may be shipped to or utilized by the licensed manufacturer.

When utilizing the short supply provisions, the supplier must ship the short supply product directly to the licensed manufacturer, or, under certain circumstances, to an authorized agent under contract with the licensed manufacturer. The supplier must maintain physical and property control over the product at all times until it is shipped to the licensed manufacturer of the final product. **

Short supply provisions also apply to a few other non-blood products.

Licensed Blood Bank Reagents and Diagnostic Products

Licensed blood bank reagents (e.g., blood grouping sera, HBsAg test kits) are under the jurisdiction of the *CBER.*

Therapeutic Exchange Plasma (TEP)

Therapeutic Exchange Plasma is the plasma obtained from therapeutic plasmapheresis. In this procedure, a patient's plasma is incrementally removed and replaced with electrolyte and/or protein solutions or plasma. The procedure is intended to remove harmful elements from the patient's circulation.

Patients undergoing therapeutic plasma exchange may suffer from a wide variety of disorders, such as autoimmune or paraproteinemic conditions, idiopathic thrombocytopenic purpura and kidney disease, and other disorders that may be associated with transmissible etiologic agents. Antibodies derived from TEP may be used only to manufacture special in-vitro diagnostic reagents which are not available from any other source.

TEP intended for further manufacture is a biolgocial product subject to the licensing provisions of section 351(a) of the Public Health Service Act.

Any firm intending to collect and ship TEP in interstate commerce for sale, barter or exchange must first obtain a U.S. license. Licensed manufacturers of Source Plasma * * must obtain a separate license for TEP, which is a different product.

It is emphasized that therapeutic plasmapheresis of a patient is a medical procedure which is used at the discretion of physicians and consequently is not within the purview of FDA. However, a firm must obtain a U.S. license when the plasma collected from the therapeutic procedure is intended or offered for sale, barter or exchange in interstate commerce for further manufacture.

*Material between asterisks is new or revised*

[] Indicates material has been deleted

Issued: 4/10/78 as 7134.14
Revised: 10/5/79, 6/18/80, 10/1/80, 11/1/83, 3/95

Sec. 230.110 Registration of Blood Banks and Other Firms Collecting, Manufacturing, Preparing or Processing Human Blood or Blood Products (CPG 7134.01)

BACKGROUND:

The November 12, 1975 Federal Register1 announced the amendment and revision of 21 CFR, Part 207 and Part 601.11 by the addition of Part 607, Registration of Human Blood and Blood Product Establishments and Listing of Blood and Blood Products. This announcement transferred administrative responsibility to the Office of Biologics Research and Review *((currently the Center for Biologics Evaluation and Research (CBER))* for the registration of blood establishments and the listing of blood products and designated form FDA 2830 (Blood Establishment Registration and Product Listing) for such purposes. *On April 1, 1984, the Drug Listing Branch, Office of Compliance, Center for Drugs and Biologics, assumed this function.*

Subsequently, Section 607² was amended to exempt transfusion services and clinical laboratories approved by the Health Care Finance Administration (HCFA) for reimbursement under its Medicare program from registration in order to reflect an FDA/HCFA interagency agreement (CPG 7155e.03) transferring routine inspection responsibility for these firms to HCFA.

To aid in the implementation of the FDA/HCFA agreement, form FDA 2830 was revised for the calendar year 1980 registration to ascertain each respondent's eligibility for exemption. Eligible firms were then exempted from further registration when the final rule exempting these facilities was published December 30, 1980. Subsequently, these exempt firms did not register in calendar year 1981. Effective October 1, 1979, the FDA was no longer responsible for routine inspection of these exempt facilities:

Clinical Laboratories - Those facilities which test donor blood or plasma for hepatitis (HBsAg), serum protein and syphilis in support of the preparation of the blood products by other establishments. In general, whether these are large firms with numerous testing contracts for plasma, or small firms doing a "followup" hepatitis (HBsAg) test on an emergency collection sample, they usually participate in a Medicare program and will be inspected by a HCFA approved certification agent.

Occasionally, a firm will consolidate "in-house" testing at a specialized location not Medicare approved. Should FDA need to inspect such laboratories, specific assignments will be issued.

Transfusion Services - A transfusion service is a hospital facility or portion of a hospital facility engaged in compatibility testing and transfusion of blood and blood products but which neither routinely collects nor processes blood and blood products (except red blood cells). If a hospital is approved by HCFA for reimbursement under one of its Medicare programs and does not routinely collect blood or process whole blood into components (except red blood cells) it will no longer be inspected by FDA except on an individual assignment basis. "Routinely" refers to functions performed on a regular basis, including autologous collections but does not include emergency or therapeutic collections. An emergency situation is that which demands immediate action, suitably documented in writing, as determined by a responsible person. In addition, transfusion services that process whole blood into plasma products, e.g., recovered plasma, intended solely for further manufacturing use will not be required to register. Freezing, deglycerolizing, washing, rejuvenating or removing the leukocytes from red blood cells are acts requiring registration. Most federal, non-military transfusion services not Medicare approved will remain the responsibility of FDA field personnel (military banks will continue to be inspected by the Office of Biologics Research and Review Personnel).

Unless exempt as above, the types of establishments that must register and the blood components and products that determine eligibility for registration include any facility which by chemical, physical, biological, or other procedures makes human blood or blood products. This includes: (1) manipulation, sampling, testing, or utilization of control procedures, whether applied to the final product or to any other part of the manufacturing process; (2) repackaging or otherwise changing the containers, wrapper or labeling of any blood or blood products package in furtherance of distribution of the product from the original place of manufacture to the person who makes the final delivery to the ultimate consumer; (3) processing (including storage under controlled conditions) and any other work that is performed on human blood or blood products themselves; (4) testing as blood grouping as well as compatibility testing when performed by a non-Medicare approved establishment in conjunction with a transfusion of blood or blood components. Accurate registration by a firm is essential so that, as appropriate, exemptions can be made.
Registration is also required of blood banks or other establishments that collect or supply blood cells, serum or plasma for the manufacture of a drug, or as a component in the manufacture of laboratory reagents and controls, including those non-Medicare approved establishments that supply outdated pooled plasma to manufacturers of fractionation products or laboratory control reagents. Finally, all establishments that manufacture plasma by plasmapheresis will be required to register, regardless of whether the plasma so manufactured is to be used for fractionation, unlicensed laboratory control reagents, licensed blood grouping serums, hepatitis associated antibody, or any other diagnostic reagents made from plasma.

POLICY:

Those blood banks and other human blood or blood product establishments required to register under Section 510 of the FD&C Act and Title 21, CFR Section 607 include:

A. Blood banks and other establishments collecting, manufacturing, relabeling, or preparing human blood, blood components, or products including establishments preparing components from blood or blood products received from other banks or sources. For example, community blood banks, hospital blood banks which collect or prepare components (except red blood cells not otherwise manipulated by freezing, rejuvenating, etc.) manufacturers of albumin, blood grouping serums, other blood diagnostic products, etc.

B. Blood banks and other non-hospital establishments that collect or prepare blood cells, serums, or plasma for further manufacture into a drug or device including components used in the manufacture of laboratory reagents or controls such as a "in-house" drawing facility for a diagnostic manufacturer.

C. All plasmapheresis establishments.

D. Establishments which store and distribute blood or blood products under specific controlled conditions such as community blood bank distribution centers and plasma brokers with storage facilities.

E. Hospital transfusion services engaged in compatibility testing which neither routinely collect (including autologous but excluding therapeutic or emergency) or prepare blood or blood products, but which are not approved for a Medicare reimbursement, such as VA, military, and some PHS hospitals.

F. Testing laboratories which are not approved for a Medicare reimbursement program such as "in-house" testing laboratories used by large source plasma fractionators.

Establishments which are solely Medicare approved testing laboratories or hospital transfusion services are not required to register.

Firms which fail to register will be identified by the Office of Compliance by assignment memo in accordance with FMD 92, part IV.D.3 by April 1, of each year. Following district office contact of each firm, a final list of firms which have failed to register will be prepared by July 1. Compliance Branches will then initiate appropriate regulatory action as required by FMD 92, part II.B.4. Districts are authorized to issued *Warning* Letters in accordance with Chapter 8-10, Regulatory Procedures Manual, when the following conditions are met:

A. The firm is required to register (this should be documented).

B. A current inspection includes an inventory of drugs (blood products on hand), and the collection of representative (documentary) samples.

C. The establishment file documents that management has been advised of the firm's responsibility to register and they have refused to do so.

D. The district has contacted the *Division of Blood Applications,* Office of *Blood Research and Review, CBER, HFM-370* to assure that no registration forms have been received. *DBA* will immediately call districts if any of the firms listed as of July register.)

To save an extra trip, it is recommended that the *Warning* Letter be prepared and delivered along with a blank registration form at the conclusion of the sample collecting inspection.

*Warning* Letters should require completion of the forms and return to the district within 10 days. Districts should forward completed FD 2830s to *HFM-370* for validation. If the *Warning* Letter fails to achieve compliance within one week after the response period expires (17 days after issuance) districts should then prepare and forward a complaint for injunction (usually a preliminary injunction citing 301(p)) to *HFM-610*.

Copies of all *Warning* Letters issued and responses should be forwarded to the *Division of Case Management (HFM-610)* within 30 days.

¹ Federal Register, Volume 40, No. 219 - Wednesday, November 12, 1975

² Federal Register, Volume 45, No. 251 - Tuesday, December 30, 1980

* Material between asterisks is new or revised*

Issued: 6/17/74
Revised: 10/1/81, 11/1/81, 12/1/82, 3/95

Sec. 230.120 Human Blood and Blood Products as Drugs. (CPG 7134.02)

BACKGROUND:

The January 31, 1973 Federal Register¹ announced the amendment and revision of 21 CFR, Part 273.² The preamble to this announcement also directs attention to the classification of blood and blood products as drugs under the Federal Food, Drug, and Cosmetic Act as well as biologics under the Public Health Service Act.

Excepts from the preamble of the January 31, 1973 Federal Register announcement responding to questions concerning the classification of blood as a drug follow:

". . . Section 201(g)(1) definition of drug in the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321), reveals that blood and related blood products fall clearly within that definition. That section states "The term 'drug' means (A) articles recognized in the official United States Pharmacopeia . . .; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals: . . ." Blood is covered by both parts of this definition. Human blood was first recognized in the United States Pharmacopeia (U.S.P.), XV Edition (Dec. 15, 1955), and has been included in each U.S.P. since that edition. Indications for use of blood products also fall directly within the broad therapeutic scope of the definition. While it is, of course, true that blood is human living tissue, it is incorrect to assume that it must be either a living human tissue or a drug. That human blood and blood products may be characterized as living human tissue for some purposes, and as biologics for purposes of regulation under the Public Health Service Act (Section 351, 58 Stat. 702, as amended; 42 U.S.C. 262) in no way alters the fact that blood is also a drug subject to regulation under applicable provisions of the Federal Food, Drug, and Cosmetic . . ."

POLICY:

Human blood and blood products are characterized as biologics for purposes of regulation under the Public Health Service Act, as amended and also as drugs subject to regulation under applicable provisions of the Federal Food, Drug, and Cosmetic Act.

¹ Federal Register Volume 28, No. 20 Wednesday, January 31, 1973

² Recodified as 21 CFR 600

Issued: 6/17/74
Revised: 10/1/80

Sec. 230.130 Adequate Space for Determination of Donor Suitability (CPG 7134.17)

BACKGROUND:

21 CFR 606.40(a)(1) requires that facilities for interviewing donors provide adequate space for private and accurate examinations of individuals to determine their suitability as [] donors. []

The Agency views privacy to include any type of arrangement that would allow the donor to answer questions without being overheard by staff and other donors. This can be accomplished in a variety of ways, e.g., special donor screening booths, partitions, or simply by using an isolated area such as the corner of the room.

POLICY:

It is not the intent of 21 CFR 606.40(a)(1) to require donor screening booths and partitions, but rather to assure that there is an arrangement whereby other donors and staff will not unavoidably overhear responses during donor suitability determinations.

[] Indicates material has been deleted

Issued: 4/8/80 as 7134.13
Revised: 10/1/80, 3/95

Sub Chapter 231 Platelets

Sec. 231.100 *Platelets, Pooled* (CPG 7134.13)

BACKGROUND:

*Platelets are* defined (21 CFR 640.20(a)) as the "platelets from a single donor ---." Investigators have encountered *Platelets*, Pooled being shipped intrastate by blood banks at the request of user hospitals. The field has requested *that the Center for Biologics Evaluation and Research (CBER) review the* policy regarding pooling of platelets during preparation or processing since it is prohibited by the regulation for the licensed product.

POLICY:

A written standard operating procedure for the pooling process must be available for personnel involved. Platelets cannot be pooled during the preparation process. After preparation of the individual units is completed (including all testing and labeling), units intended for a specific patient may be pooled and labeled with an expiration time of four hours from time of pooling. This expiration time must also take into account the dating period of the individual units.

In addition to the labeling requirements in 21 CFR *606.121,* the label of the pooled product must include the following:

1. An expiration time which is four (4) hours after the platelets are pooled.

2. The individual donor numbers comprising the pool or a pool number that relates the pooled platelets to individual donor numbers comprising the pool.

3. The number of units in the pool.

*Material between asterisks is new or revised*

Issued: 4/26/78
Revised: 10/1/80, 4/1/82, 3/95

Sec. 231.110 Quality Control Testing of *Platelets* [] and Cryoprecipitated Anti-hemophilic Factor [] (CPG 7134.16)

BACKGROUND:

The *Center for Biologics Evaluation and Research (CBER)* has re-evaluated the requirements of 21 CFR 640.25(b) and 640.56(a). These sections state that each month 4 units of *Platelets* [] and Cryoprecipitated Antihemophilic Factor [] prepared from different donors, shall be quality control tested. This has previously been interpreted to mean every month, even when *Platelets* [] and Cryoprecipitated Antihemophilic Factor [] are not prepared for clinical use by the blood bank. *However, CBER* believes that quality control testing of the product need be performed only in the months that the product is prepared for use.

POLICY:

Quality control testing and assay, at the end of the dating period, for *platelets* [] need be performed only in those months in which *platelets* [] are prepared for use. Similarly, Cryoprecipitated Antihemophilic Factor [] quality control testing need only be performed during months in which this product is prepared for use.

*Material between asterisks is new or revised*

[] Indicates material has been deleted

Issued: 12/26/78 as 7134.17
Revised: 10/1/80, 4/1/ 82, 3/95

Sec. 231.120 Time Period for Separation of Platelets from Platelet-Rich Plasma when Preparing *Platelets* and Fresh Frozen Plasma* (CPG 7134.20)

BACKGROUND:

Section 640.24(b) of 21 CFR requires that *Platelets* [] shall be separated within 4 hours after the collection of the unit of whole blood or plasma.

During inspections, questions have arisen concerning blood banks that do not separate the platelets from platelet-rich plasma for a period in excess of 4 hours.

This section of the regulations was promulgated to assure that the red cells are promptly separated from the plasma and refrigerated rather than concern about compromising the quality of the resultant platelet concentrate if the platelets remained in the plasma for a period in excess of four hours.

Based on recommendations received from the Panel on Safety and Efficacy of Blood and Blood Derivatives, the *Center for Biologics Evaluation and Research* is preparing to modify the regulation to indicate that:

a. The 4-hour period for separation of plasma from red cells be changed to 6 hours. (Please note--The plasma should be placed in the freezer within 6 hours. 21 CFR 640.34(b), which requires that plasma be frozen solid within 6 hours, will be revised to reflect this change)

b. There be no time limit set for the preparation of *platelets* from platelet-rich plasma.

POLICY:

*Platelets* [] may be prepared from platelet-rich plasma at any time during the dating period assigned to *platelets,* provided that:

1. Not more than 6 hours following collection of whole blood, the red cells are separated from the platelet-rich plasma and refrigerated;

and

2. The platelet-rich plasma is stored at the appropriate temperature (20-24^o C) until the platelets are separated.

Blood banks that prepare *Platelets* [] and * * Fresh Frozen *Plasma* consistent with these policy guidelines will not be considered to be deviating from acceptable manufacturing practices.

*Material between asterisks is new or revised*

[] Indicates material has been deleted

Issued: 7/1/82
Revised: 12/1/82, 3/95

Sec. 231.130 Storage of *Platelets* [] for up to five (5) days (CPG 7134.21)

BACKGROUND:

The *Center for Biologics Evaluation and Research (CBER)* has approved plastic materials for satellite packs designed for storage of *Platelets.* [] These materials [] allow the storage of platelets for up to five (5) days if stored at 20-24^oC with gentle agitation. With this approval for five day storage, two dating periods apply to platelets stored in satellite packs. The satellite packs made from the plastic materials are labeled with a statement indicating that platelets may be stored for five days if stored at 20-24^oC. If this label does not appear on the pack the previously approved 72-hour dating still applies.

POLICY:

Blood banks may begin the five (5) day dating period (the dating period ends on midnight of the fifth day; e.g., platelets collected at any time on Monday the first will expire on *Saturday* the sixth at midnight) for *Platelets* [] stored at 20-24^oC, with gentle agitation, in the satellite packs provided:

1. A product license *supplement* reflecting the change in the dating period is submitted, including a commitment to perform the required quality control testing at the end of the dating period (5 days) on at least four (4) units per month. (Also, see CPG No. 7134.16 (See Sec. 231.110) concerning QC testing on platelets).

2. Corrective action is implemented as soon as possible and is appropriately documented, if the quality control data do not meet required limits.

3. The monthly quality control data are kept on file in the blood bank available for review during authorized FDA inspections.

4. *Repeated* failure to meet [] quality control standards is reported immediately to *CBER.*

Unlicensed, registered blood banks may use the satellite packs and the five (5) day dating period without notifying *CBER* provided they outlined in (1)-(4) above, *except that unlicensed blood banks need not file or supplement a product license* [See 21 CFR 606.160(b)(2)(ii) and 640.25(b)]. []

*Material between asterisks is new or revised*

[] Indicates material has been deleted

Issued: 7/1/82
Revised: 3/95

Sub Chapter 250 - 256 Plasma

Sec. 250.100 Source Plasma [] Guidelines for Informed Consent Forms (CPG 7134.08)

BACKGROUND AND POLICY:

Informed consent is the agreement obtained from a subject, or the subject's authorized representative, for the subject's participation in the specific program. Donors who are considering entering a plasmapheresis program must be made aware of the nature of the procedure and of all its risks. In addition to a verbal explanation which a licensed physician is required to provide, the individual should have the opportunity to read, as well as hear the details of the procedure so he/she is, indeed, informed. The agreements shall contain no exculpatory language through which the donor is made to waive, or appear to waive, any of his/her legal rights, or to release the corporate establishment or its agents from liability for negligence. Two separate consent forms should be available, one for the regular plasmapheresis procedure, and one for immunization.

A. Each form should include the following:

1. A clear explanation in non-medical terms, of the procedures to be followed, including maximum volumes of blood to be removed at one time, and the time limits between donations set forth in the Regulations.

2. A description of any donor's discomforts and the risks of the procedure including:

a. Possible return of another donor's red blood cells resulting in a hemolytic transfusion reaction;

b. Common systemic reactions which may ensue;

c. Changes in protein, hemoglobin, IgG levels which may necessitate deferment or removal from the program.

3. The necessity for a donor to actively participate in accurate identification of his/her red blood cells before they are returned to him/her.

4. The statement that the donor has been offered an opportunity to ask any questions concerning the procedures or an opportunity to refuse, before a consent form is signed.

5. An instruction that the donor is free to withdraw his/her consent and to discontinue participation in the plasmapheresis program at any time.

B. If plasmapheresis is to be accompanied by immunizing injections, the form shall also include:

1. A clear explanation of the immunization program including:

a. The nature of the antigen(s) which will be used. (Space should be provided on the form for the identification of each antigen to be administered);

b. Approximate duration of the immunization program;

c. Maximum number of injections and factors determining when injections will be administered.

2. If the immunizing agent is a human blood product, the donor should be made fully aware of the following:

a. The possible transmission of hepatitis viruses;

b. the increased risk of adverse reaction if incompatible blood is received by the donor at a later date;

c. women of childbearing age should not be immunized unless evidence of surgical sterility is presented;

d. the increased risk of rejecting an organ transplant, if such a transplant is needed at a later date.

*Material between asterisks is new or revised*

[] Indicates material has been deleted

Issued: 7/19/76
Revised: 10/1/80, 3/95

Sec. 250.500 Plasma Brokers - Registration and Compliance with Good Manufacturing Practices (CPG 7134.22)

BACKGROUND:

Compliance Policy Guide (CPG) Number 7134.01, *(Sec. 230.110)* Registration of Blood Banks and Other Firms Collecting, Manufacturing, Preparing or Processing Human Blood or Blood Products, provides extensive background regarding registration requirements. The purpose of this CPG is to emphasize that plasma brokers are required to register as stated in CPG No. 7134.01 (See Sec 230.110). The agency has not, in the past, focused heavily upon these establishments, however, the number of problem situations involving plasma shipped through brokers has increased. For example, recalls of biological products have occurred in which plasma brokers have been subdistributors. In at least one of these recalls consignees of the suspect products could not be determined due to inadequate or unavailable plasma broker's distribution records.

POLICY:

Plasma brokers that take custody of products are required to register pursuant to 21 CFR Part 607 and must comply with applicable sections of 21 CFR. Sections 606.100 (b)(10) & (18), 606.160 (b)(3)(i) and (iii) and 606.165 are particularly applicable to plasma brokers. Brokers that only handle paperwork and do not take custody of the product are not required to register and, therefore, need only have records showing transfer of the biological product from the manufacturer to the consignee.

REGULATORY ACTION GUIDANCE:

The following represent criteria for direct reference issuance of *Warning* Letters by district offices:

a. The firm is required to register and the establishment file shows that management has been advised of the registration requirement, but has failed to comply. NOTE: The district must contact the *Division of Blood Applications, Office of Blood Research and Review, Center for Biologics Evaluation and Research (CBER) (HFM-375),* to assure that no registration forms have been received.

or

b. A current inspection of the broker, whether registered or not, shows that the firm has substantive deviations from the area of CGMPRs listed above under "POLICY" such as non-traceability of units in distribution or to original donors; inadequate storage conditions, or any others applicable to the operations in which the firm is engaged.

*Warning* Letters should contain a statement advising the firm that registration is required and include the necessary forms for completion and return to the district within 10 days. Districts should forward completed FD 2830s to *HFM-370* for validation.

If the *Warning* Letter fails to achieve compliance within one week after the response period expires (17 days after issuance), districts should prepare and forward a complaint for injunction [usually a preliminary injunction citing 301(p) of the Federal Food, Drug, and Cosmetic Act] in accordance with Agency procedures.

Deficiencies from standard operation procedures generally would not be a basis for injunction.

If the *Warning* Letter issued cites 501 (a) (2) (B) charges, the district should follow Chapter 8-10 in the Regulatory Procedures Manual.

Copies of all *Warning* Letters issued and responses should be routinely forwarded to the *CBER, Division of Case Management (HFM-610)* and Division of *Compliance Policy (HFC-230)* within 30 days of issuance or receipt.

*Material between asterisks is new or revised*

Issued: 2/1/84
Revised: 3/95

Sec. 251.100 Schedule of Physical Examination for Donors Receiving Immunization Injections (CPG 7134.18)

BACKGROUND:

Confusion has arisen regarding the interpretation of 21 CFR 640.63(b)(2). The purpose of this regulation is to prevent plasmapheresis centers from immunizing donors without first giving them a physical examination.

POLICY:

An active plasmapheresis donor who is to be immunized and who has already received a physical examination pursuant to 21 CFR 640.63(b)(1), need not be re-examined for immunization provided that the donor:

1. is certified by the examining physician as suitable to be an immunized donor,

2. receives the physician's explanation of the hazards of immunization,

and

3. signs an informed consent form for immunization.

A donor who is to be immunized and who is not already in a plasmapheresis program, must be given an initial medical examination no more than one week before the first immunization injection, in addition to 1 thru 3 above. The medical examination for plasmapheresis need not be repeated if the first donation occurs within 21 days after the first injection.

Issued: 10/1/80

Sec. 252.100 Source Plasma [] - Regulatory Action Based on Overbleeding (CPG 7134.14)

BACKGROUND:

The *Center for Biologics Evaluation and Research (CBER)* has re-evaluated the health hazard criteria associated with overbleeding plasmapheresis donors, based on current scientific evaluations.

A substantial degree of deviation from the requirements [21 CFR 640.65(b)(4), (5) and (6)] is significant. Critical factors that are to be considered in determining overbleeding by volume are: 1) the volume (normally converted from weight) of whole blood collected at one time or within a specified period of time (2 days and/or 7 days); and 2) the volume of plasma obtained from whole blood collections. The precision of blood weight and volume determinations may be affected by factors such as biologic variability of the donors, human errors in blood collection, variability in bag weights, accuracy of the scales, and the amount of anticoagulant.

POLICY:

1. Whole Blood Volumes

Overbleeding is considered significant when: a) the volume of whole blood removed routinely exceeds the maximum allowable limits in 21 CFR 640.65(b)(4), (5) and (6); or b) there is no indication that overbleeding is recognized and corrected.

2. Plasma Volumes

Overbleeding is considered significant when the volume of units of Source Plasma routinely exceeds the maximum allowable limit of 770 mls (790 gms) for donors weighing less than 175 pounds and 925 mls (949 gms) for those weighing 175 pounds or more. (Plasma collected in heparin solution will have a lower yield).

NOTE: Documentation must establish a pattern of conduct over a period of time which illustrates a normal or customary (routine) practice of overbleeding.

REGULATORY ACTION GUIDANCE:

Overbleeding, as described above, coupled with significant deficiencies in determining donor suitability, described below, warrants considering recommendation for suspension of activities under U.S. license.

A. Personnel unfamiliar with or improperly determining hematocrit, blood pressure, temperature, or total protein (T.P.).

B. Refractometer for determining T.P. not adequately cleaned between determinations or malfunctioning and correct readings cannot be obtained.

C. Donors plasmapheresed whose plasma protein composition was outside the normal range established by the testing laboratory.

*Material between asterisks is new or revised*

[] Indicates material has been deleted

Issued: 8/1/78 as 7134.16
Revised: 10/10/78, 10/1/80, 7/1/82, 3/95

Sec. 253.100 Use of Units of *Plasma and Fresh Frozen Plasma* Which Have Been Thawed (CPG 7134.19)

BACKGROUND:

As prescribed by 21 CFR *606.122(m)(3),* the product *labeling* states that *frozen plasma* products should be used within six hours after thawing. However, some blood banks have been extending this time for as much as 26 days and using the plasma as a blood volume expander for transfusion.

The Blood Products Advisory Committee has made a recommendation to the *Center for Biologics Evaluation and Research (CBER)* that *Fresh Frozen Plasma* should be allowed for transfusion within 24 hours after thawing. The *CBER* is planning to change the regulation to allow for the transfusion of the *thawed Fresh Frozen* Plasma within 24 hours.

POLICY:

Until such time that the regulation is changed, *frozen plasma products* should be transfused within six hours of thawing. If not transfused within the six hours, the thawed plasma may be relabeled and used as Recovered Human Plasma for further manufacturing.

Failure to transfuse the product within the six hours will continue to be a deviation from 21 CFR *606.122(m)(3).* However, this deviation alone will not be considered to be of the significance which would warrant a recommendation for regulatory action.

*Material between asterisks is new or revised.*

Issued: 10/1/80
Revised: 3/95

Sec. 254.100 Source Plasma [] - Use of Units from Donors Subsequently Found to be Reactive to a Serologic Test for Syphilis (CPG 7134.15)

BACKGROUND:

There has been some concern and confusion relating to the use of units of Source Plasma * * collected from donors who are subsequently found to be reactive to a serologic test for syphilis (STS). The initial and four-month STS is designed primarily to identify the disease in donors and to promote treatment of affected donors; therefore, the donor, once identified as STS reactive, may not obe plasmapheresed again until his/her serologic test is nonreactive or collection is performed under the provisions of 21 CFR 640.65(b)(2)(iii) and (iv). These provisions permit, under certain conditions, plasmapheresis of donors with biologic-false-positive reactions; or those with positive results. However, units collected from donors prior to their being identified as STS reactive may be issued as Source Plasma, [] since the disease-causing spirochetes are destroyed during the storage and/or fractionation of the plasma.

POLICY:

Units of plasma collected from plasmapheresis donors who were not known to be reactive to a STS prior to the plasmapheresis procedure may be shipped as Source Plasma []. These units need not be labeled or identified in shipping records as STS reactive, since such requirements pertain only to units collected from donors known to be STS reactive.

*Material between asterisks is new or revised*

[] Indicates material has been deleted

Issued: 3/14/80 as 7134.11
Revised: 10/1/80, 2/1/84, 3/95

Sec. 255.100 Quantitative Testing for Serum Proteins in Plasmapheresis Donors (CPG 7134.10)

BACKGROUND:

Investigators have reported deviations from Section 640.65(b)(2)(i) of Title 21, Code of Federal Regulations regarding the quantitative testing of serum or plasma by electrophoretic or immunodiffusion techniques to determine protein composition, and the interpretation of the results. To clarify the position of the *Center for Biologics Evaluation and Research (CBER)* and to prevent misinterpretations with respect to Section 640.65(b)(2)(i), the following policy is stated:

POLICY:

1. The normal ranges established by the testing laboratory for protein composition must be expressed with a minimum and maximum value for each protein fraction. A total protein test should also be performed on the same Sample by the laboratory performing quantification tests. The total protein value must be no less than 6.0gm/100ml.

2. A donor may be continued on the program only if the results of the serum protein electrophoresis or the immunoglobulin diffusion test fall within the ranges established by the testing laboratory. If the value of any protein fraction is reported outside this established range, the donor must be removed from the program until another sample is drawn, retested and all values are reported to fall within the established range. If the results are not within the established range, the physician at the plasma center does not have authority to allow a donor to continue on the plasmapheresis program.

*Material between asterisks is new or revised*

Issued: 8/6/76
Revised: 10/1/80, 3/95

Sec. 256.100 Plasmapheresis - 48-hour Period Between Plasmapheresis Procedures (CPG 7134.23)

BACKGROUND:

The *Center for Biologics Evaluation and Research (CBER)* has received inquiries about the required 48-hour period between plasmapheresis procedures contained in 21 CFR 640.65(b)(4). Some investigators have interpreted the 48-hour period to be two days and some investigators have interpreted the requirement to be not less than 48 hours.

One recommendation coming from the ongoing Retrospective Review of Biologics Regulations is that the wording for this 48-hour period be changed to read two days. *CBER* agrees with this recommendation and is moving to change the wording in the regulations.

POLICY:

The required 48-hour period is two calendar days, regardless of the time of day that the donor is plasmapheresed.

*Material between asterisks is new or revised*

Issued: 5/1/84
Revised: 3/95

Sub Chapter 270 - 275 Non-Blood Products

Sec. 270.100 Final Container Labels - Allergenic Extracts Containing Glycerin; Reporting Changes (CPG 7134.06)

BACKGROUND AND POLICY:

It has come to our attention that not all manufacturers indicate on the container labels whether or not the allergenic extract contains glycerin. Since preparations containing glycerin cannot be injected without discomfort, many allergists do not inject such extracts. Therefore, as an added item of important information, manufacturers who prepare glycerinated allergenic extracts, must indicate on the container label, the presence of any amount of glycerin in the final product.

Secondly, in accordance with "Changes To Be Reported - 21 CFR 601.12", we wish to emphasize that the *Center for Biologics Evaluation and Research* must be notified regarding any proposed changes in labeling and manufacturing methods *for any licensed biologocal. Such changes include the addition of* any new allergenic extract to *a licensed* manufacturer's listing of approved extracts. Such changes may not become effective until notification of acceptance is received from *CBER [i.e., approval of a supplement to the establishment license application (ELA) or product license application (PLA)].*

Issued: 7/19/76
Revised: 10/1/80, 4/1/82, 3/95

Sec. 275.100 Immune Milk (CPG 7134.04)

BACKGROUND:

Immune Milk was developed by W. E. Peterson, Ph.D., Professor of Dairy Science, at the University of Minnesota. The product is prepared by giving cows a series of intramammary infusions of polyvalent antigens comprising phenol-killed bacterial pathogens. The antigen is infused at weekly intervals, by the teat canal into the udder tissues, four times before the cow freshens. The milk is collected, processed by pasteurization and kept in a frozen state until used.

Immune Milk has been recommended for such human disease conditions as rheumatoid arthritis, gastroenteritis, urinary tract and sinus infections, certain types of allergies, and chronic neurologic conditions (i.e. multiple sclerosis).

POLICY:

Immune Milk is regarded as a biologic drug and subject to the licensing provisions of the Public Health Service Act, administered by the *Center for Biologics Evaluation and Research.* To date, no establishment or product licenses have been issued for this product. Any shipments of such products should be brought to the attention of the *Center for Biologics Evaluation and Research.* for the purpose of initiating appropriate regulatory action. The following are currently active INDs for immune milk products:

IND NUMBER          SPONSOR

546 Impro Products, Inc., Waukon, Iowa 

857 & *1920*        Stole Research and Development Corporation, Cincinnati, Ohio

*1774               Richard McClead, M.D. 
    Columbus, Ohio* 

*Material between asterisks is new or revised*

Issued: 6/23/76
Revised: 10/1/80, 4/2/82, 3/95