HISTORY OF YELLOW FEVER- OPENING OF PANAMA CANAL

On July 22, 1905 , Harper's Weekly featured a cartoon about the problem of yellow fever during construction of the Panama Canal

In all of ancient medical literature there is no reference to Yellow Fever, by that or any other name. Since epidemic yellow fever is a dramatic disease, it seems unlikely that it could have escaped the attention of even very early medical writers. It is perhaps reasonable to conclude that the disease did not exist in ancient civilizations (Warren, 1951).

          There are reports of disease with clinical description similar to yellow fever in 1498 in San Domingo and 1585 in West Africa (Scott, 1939). Carter found the earliest record in a Mayan manuscript describing an epidemic with hematemesis (black vomit, or “xekik”) in the Yucatan in 1648, and suggested that the virus and mosquito vector were introduced from Africa during the slave trade (Carter, 1931).

          According to Garrison (1929) the term yellow fever was first employed by Griffin Hughes in his “Natural History of Barbados” (1750). The yellow in yellow fever does not indicate the association of the disease with jaundice but is derived from the yellow quarantine flag used by the ships during the 17^th century (Singh and Bhatia, 1993).

          Yellow Fever was responsible for several epidemics among the settlers in tropical areas of the Americas and Africa during the 17^th to the 19^th centuries. In addition, epidemics were also reported in Europe following importation of the virus in sailing ships. However, the origin of the disease is in doubt but the susceptibility of ‘New World Monkeys’ but not African monkeys to latent infection by yellow fever indicates African origin of disease (Monath, 1994).

          Until the 20^th century, yellow fever was widely believed to be an airborne “miasma” arising from filth, sewage, and rotting organic matter. The series of developments thereafter in disease etiology, etiological agent, epidemiology and vaccine are given below:

1848:

          View, that spread of yellow fever required the presence of an intermediate host, appears to have first advanced by Dr. Josiah Clark Nott of Mobile, Alabama. Nott suggested the mosquito as a possible agent for the dissociation of both yellow fever and malaria (Warren, 1951). Dr Louis Daniel Beauperthuy in Venezuela made a similar suggestion in 1854.

1880:

          The first attempt to dig Panama Canal in 1880-88 failed after 52000 cases of yellow fever and malaria were reported among the 85000 workers (Bres, 1986).

1881:

          The first really serious proponent of the mosquito transmission in yellow fever was Dr. Carlos J. Finlay of Havana, Cuba (Warren, 1951; Burke and Monath, 2001; WHO, 1998).

1897:

          Dr. Giuseppe Sanarelli, an Italian bacteriologist working in the islands of Flores off Montevideo announced that he had discovered the cause of yellow fever to be a bacillus present in about 50% of patients examined by him. He named it Bacillus icteroides (Sanarelli, 1897).

1900:

          In May United States Army organized a commission to study the infectious diseases of Cuba but more specifically yellow fever. Dr. Walter Reed was appointed as president.

          Dr. Reed and colleagues from their studies concluded that “Bacillus icteroides” stand in no causative relation to yellow fever, but when present should be considered as a secondary invader in this disease” (Reed, Carrol et. al., 1900).

          Influenced by the work of Sir Ronald Ross and of Italian observers on the propagation of malaria by the mosquito the commission directed their attention on the Finlay’s theory of the propagation of yellow fever by mosquito (Warren, 1951).

          The Reed Commission recorded 3 cases of yellow fever transmission by mosquitoes that had fed previously on patients clinically ill with yellow fever.  Subsequent work of the commission proved conclusively that:

a)              the mosquito was a vector of yellow fever;

b)             there was an interval of about twelve days between the time the mosquito took an infectious blood meal and the time it could convey the infection to another human being;

c)              yellow fever could be produced experimentally by subcutaneous injection of blood taken from the general circulation of a yellow fever patient during the 1^st and 2^nd days his illness; and

d)             yellow fever was not conveyed by fomites.

          In the consequence of these findings, Reed and his coworkers (Dr.James Carrol, Dr.Jesse, W.Lazear, and Dr.Aristides Agramonte) suggested that the spread of yellow fever could be most effectively controlled by antimosquito measures and the protection of sick from the bites of mosquitoes (Reed, Carrol and Agramonte, 1901).

1901:

          On October 15, Reed and Carrol injected subcutaneously 3cc of diluted filtered serum from an experimentally infected yellow fever patient into three non-immune persons. Two of these developed clinical yellow fever (Reed and Carrol, 1902).

          Thus for the first time a filterable virus was proved to be the cause of specific human disease.

          In February the Chief sanitary officer in Havana, then Major William C. Gorgas instituted measures to wipe out yellow fever which were based entirely on conclusions of the yellow fever commission.          The results were as dramatic as the scientific findings of the commission. By September, 1901 the disease had been completely eradicated, and it has not reappeared. The antimosquito measures in Havana, in addition to eliminating yellow fever, greatly reduced the incidence of malaria. Gorgas in Panama applied similar approach. Eradication of yellow fever from Panama led to the resumption of work of Panama Canal in 1904 and its completion in 1914 (Warren, 1951).

       

           The Havana and Panama campaigns now constitute an epic chapter in the history of sanitation and preventive medicine.

1913:

          The Rockefeller Foundation was organized for “the well-being of mankind throughout the world”.

          The International Health Commission of the Foundation was created the same year, with Mr. Wickliffe Rose as its director.

          The foundation began its work when the real danger of spreading the disease to countries with high density of population, such as India and Far Eastern countries became obvious as a consequence to the opening of the Panama Canal. Dr. S. P. James of the Indian Medical Service made a thorough investigation of the situation on behalf of the Indian Government and reported that the menace was sufficiently great to call for a permanent quarantine force in Panama, Hong Kong or Singapore, to be maintained at the expense of the English colonies in the East.

         

          Fortunate we are that the disease has not reached India so far, although Aedes ageypti is found in abundance in this country.

Rockefeller Institute of Medical Research















Panama Canal Route Map

Why has Yellow Fever never been seen in Asia?

https://thyagohills.deviantart.com/art/Yellow-Fever-virus-633704160 (Image Link)

This question has been raised since the opening of Panama Canal (August 15, 1914).

It was known at that time that the biologic environment for Yellow Fever propagation and maintenance appears to be favorable, A.aegypti is widely distributed, and susceptible animal hosts, both man and monkey, are abundant. There is no evidence that the people of India posses any racial resistance to infection with yellow fever virus or unusual tolerance to the disease. The rhesus monkey of India is one of the most susceptible of all the primates and is much less tolerant to the disease than any of the African monkeys.

Richards in 1951 proposed the probable explanation of the absence of the disease in India or elsewhere in the tropical Far East is that the virus was never introduced. Formerly there were two overseas routes that the virus might have taken in reaching India from Africa- the more direct route from the east coast of Africa to India, and the longer route from the west coast around the Cape of Good Hope. Though immunity surveys have revealed the existence of immunes in East African ports, the proportion of immunes is low. These low immunity rates imply that the disease is infrequent and rarely, if ever, reaches epidemic proportions. Under such conditions the chances that the most direct route from East Africa might convey the disease are not very great. It has been pointed out that rather special conditions are required for overseas transport, and the longer the voyage the less likely that these conditions will be fulfilled. The voyage from tropical West Africa to India is long, and in rounding the cape climatic conditions are frequently encountered that are unfavorable to the survival of the mosquito vector. Theoretically, the risk of yellow fever in Asia is greater now than in the past because of rapid modern transport, which can introduce viraemic persons or infected mosquitoes in any of the receptive areas. Experimentally, A.aegypti mosquitoes collected in different places of Asia are able to transmit the virus to monkeys or newborn mice with variable success, depending on their origin and the strain of virus utilized. This conclusion has been extended to some other Asian mosquitoes such as A.pseudoscutellaris, A.polynesiensis and might be applicable to A.albopictus (Bres, 1986). Today, the possible reasons for its absence include both demographic and biologic factors.

Hypotheses include:

· Yellow Fever occurs in remote areas and affects individuals engaged in subsistence farming, who are infrequent international travelers.

· Biologic factors that limit the risk of introduction include cross-protection, principally by dengue, against which nearly all persons residing in Asia are immune.

· A third hypothesis is that A.aegypti strains in Asia have low vector competence for yellow fever virus (Aitken et al., 1977).

It is likely that all three mechanisms combine to reduce the likelihood of introduction and spread of yellow fever virus in Asia (Monath, 2004).

Refrences:

1. Richard M. Taylor (1951): Epidemiology. In: Strode G.K. (ed). Yellow Fever,McGraw Hill, N.Y.

1. Bres, P.L.J. (1986): A century of progress in combating yellow fever.Bulletin of WHO. 64: (6), 775-786.

1. Aitken T.H.G., Downs W.G., Shope R.E (1977): Aedes aegypti strain fitness for yellow fever transmission. Am.J.Trop.Med.Hyg.26: 985 – 989.

1. Monath Thomas P. (2004): Yellow Fever Vaccine. Chapter 41. In Plotkin S.A. and Orienstein W.A.    Vaccines 4^th edition. Saunders

Material Control Strategies in Product Development

https://www.pda.org/pda-europe/news-archive/full-story/2015/01/05/raw-material-control-strategy-key-to-overall-control

Section 501 (21 U.S.C. 351) is amended by adding at the end the following flush text: ‘‘For purposes of paragraph (a)(2)(B), the term ‘current good manufacturing practice’ includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.’’.

INTRODUCTION:

Selection of raw materials and excipients to be used in manufacturing process and identification of critical material attributes to define material control strategies at development stage of product life cycle, this includes the following:

·         Discovery research (including all stages of clone development) and

·         Toxicology studies

All users involved in vector development, clone development and process development shall follow the procedure defined below.

Note: As activities of clone development are considered as critical for product lifecycle, a diligent material control with traceability of materials used in each stage shall be demonstrated (Refer ICH Q5B & Q5D and EP 5.2.12).

CONTROL STRATEGY:

MATERIAL CLASSIFICATION:

Biological product development and manufacturing uses diverse range of raw materials. These materials can be categorized as below:

A.   Base on composition materials can be categorized as:

·         Inorganic Salts and liquids,

·         Organic Salts and liquids,

·         Complex chemically defined mixtures of organic/ inorganic origin),

·         Complex materials of biological origin, including animal origin (defined),

·         Complex materials of biological origin, including animal origin (undefined),

·         Complex semi defined mixtures (containing above materials),

Note: In addition to above category there are few fixed materials used in process which though are not categorized as raw materials but are product contact and have tendency of leaching (process) impurities in the product e.g., filters and TFF membranes, chromatography media etc. Criticality of such materials shall be assessed and capture in process development report as part of process impurities.

B.   Based on usage in manufacturing process materials can be categorized as:

·         Product contact materials and

·         Product non-contact materials (such as cleaning agents)

However, there are chances of product contamination through product non-contact materials if cleaning procedures are not validated and may directly impact the product CQAs.

C.   Based material control strategy the materials used in manufacturing process can be classified as under:

·         Biological Starting Materials

·         Raw Materials

·         Drug Substance (Active Pharmaceutical Ingredient)

·         API Starting Material

·         Excipients

Note: Specific requirements for Biological Starting material are outside scope of this document.

MATERIAL CONTROL STRATEGY:

Material control at development stage is limited to first two elements; other elements shall be covered in the subsequent stages of product life cycle.

Elements of material control strategies ensure the safety (including risk of adventitious agent contamination), quality and efficacy of the biological molecule to be manufactured. These are:

1.    Selection of material and understanding the role of the raw materials in the process and criticality assessment of material

2.    Identification of material quality attributes

3.    Developing material testing strategies to ensure raw material quality and evaluating specific tests to ensure consistent material quality

4.    Setting up material/supplier risk assessments for supplier qualification program

5.    Having a supplier qualification system in place which assesses all risks of a raw material: origin risk (safety), supply risk (availability, back-up options, audits, contractual agreements) and quality risk (testing, evaluation of lot-to-lot consistency).

Note: All the elements shall be revisited during initiation of cGMP manufacturing operations such as MCB and WCB preparation, clinical batch manufacturing, process performance qualification (validation) batch manufacturing and commercial manufacturing.

SELECTION OF MATERIAL AND CRITICALITY ASSESSMENT:

Material for each process stage shall have scientific basis for selection and following criteria shall be considered:

1.    Role of material in process stage

2.    Impact of the material on quality attribute of the subsequent stage product

3.    Introduction of impurities in manufacturing process (including adventitious agents).

To ensure material control, user shall perform material risk assessment as per the table below:

Sr. No	Assessment Question	Answer (Yes/No)	Risk (High/Medium/Low)	Comments/ Justification
1	Is the RM complex?
2	Is the RM well defined?
3	Is the material of animal/human origin?
4	Is the TSE/BSE assessment available?
5	Is the RM added in the late steps of the process?
6	Is there a need to demonstrate that the process will reduce the RM level to a safe residual level?
7	Is a relevant analytical method available to assess its clearance?
8	Is the level of quality of RM susceptible to impact product CQA?
9	Is the production process of the RM generating high variability in the RM quality attributes
Remarks: (For additional assessment and comments)
Raw Material categorized as: Critical ¨   /   Non-Critical ¨
Note 1: Excipients are not accessed based on above criteria. Procedure for excipient selection and assessment is provided below. Note 2: Assessment shall be performed for all raw materials, including chromatography resins and media. In column for ‘Answer’ enter ‘Yes’ or ‘No’, identify the risk associated in each evaluation step and provide comments and justification for each risk categorized (irrespective of low, medium, high) with current and recommended mitigation plan.

From the above assessment a list of critical and non-critical materials will be generated.

FOR CRITICAL MATERIALS: Higher grade material with more control on material attributes shall be selected, preferable to use compendial grade material manufactured under cGMP environment.

FOR NON-CRITICAL MATERIALS: Grade of material is flexible however consistency in supply of material with identified attributes shall be ensured.

SELECTION OF EXCIPIENTS:

Excipients are added for the purpose of production enhancement, patient acceptability, improving stability, controlling release etc. Though termed as inactive components, excipients can have an impact on the absorption, distribution, metabolism and elimination process of the co-administered drug, which is important information when selecting excipient for any formulation.

As manufacturer of the chemicals supply their material for different applications and end users (such as cosmetics, food additives etc.), it is responsibility of the user to select the excipient of appropriate type and grade to meet additional quality functionality and safety requirements.

Below are the basic check points used during selection of excipients:

1.	Name of the excipient in the formulation:
2.	Is the excipient complex chemical: (Define physical and chemical properties, material (excipient) specifications including impurities and residual solvent)
3.	Is the excipient well defined: Define physical and chemical properties, material (excipient) specifications including impurities and residual solvent)
4.	Is the proposed material (excipient) of animal/human origin:
5.	Is the production process of the material (excipient ) anticipated to generate high variability in the quality attributes:
6.	Is the level of quality of material (excipient) susceptible to impact product CQA. List and define critical material attributes (CMA) of the material (excipient):
7.	Is the TSE/BSE assessment available for the excipient:
8.	Mention role of material (excipient) in the formulation (such as diluent, buffering compound, antioxidant, stabilizer, enhances solubility, enhances bioavailability etc.):
9.	Mention intended route of administration of finished product (topical, ophthalmic, oral, parenteral etc.):
10.	Is the material previously selected as excipient for intended route of delivery:
11.	Is the proposed material identified as established excipient: (If yes, in which IPEC category does it fall) 1.    Existing chemical excipient- first in human: (These are class of excipients where animal safety data does exist, as data may have been used in  another regulatory applications) 2.    Existing chemical excipient: (These are excipients that have been used in man, but for another route of administration, higher dose etc., and additional safety may be required) 3.    New modification of existing excipient: (Established excipient is the new modifications of combinations, which would not require safety evaluation)
12.	Is the excipient approved by any of the regulatory agencies: (Refer different resources and mention wherever listed, such as EMA's Excipients Drafting Group (ExcpDG), FDA Inactive ingredient database, Safety and Toxicity of Excipients for Paediatrics (STEP) Database, listed in GRAS database, FAP database, wherever available DMF File number shall be provided).
13.	Is an official monograph available in any of Pharmacopeia (USP-NF, EP, JP, IP etc.):
14.	Is the material identified as new chemical excipient:
15.	Does the selected vendor follow IPEC (The International Pharmaceutical Excipients Council) cGMP Guidelines:
16.	Does the selected vendor has ISO 9001 certification:
17.	Does the selected vendor has EXCiPACT certification:
18.	Does the selected vendor material meet the designated Pharmacopeial requirements, if yes, mention the pharmacopeia (attach monograph copy):
19.	Note: Though supply security and quality agreements are not expected during discovery research and toxicology studies, however given the criticality of the excipient and impact of change on regulatory filing, wherever possible below expectations shall be ensured: ·         Manufacturing process for excipient shall be sought from vendor, ·         Understanding with the manufacturer to ensure change notification in manufacturing process and CQA of material ·         Long term supply commitment Note: Regulatory filing process for new excipients is outside the scope of this document.

User shall compile all the above information with relevant evidences as annexures in single report for excipient selected.

MATERIAL CONTROL STRATEGY

As the scope of this document is limited to discovery research and toxicology studies, material control strategy for these stages is defined below.

Drug Discovery:

·         Material and vendor selection as per study plan (assessment defined in 5.3.2 can be performed and recorded)

·         COA and expiry of all incoming process material documented for use in relevant documents (LNBs, protocols & records etc.)

·         Material (Safety Data Sheet) (MSDS/ SDS) understood and to be made available at site of usage for ready reference along with COA.

·         Storage and expiry as per vendor recommendation.

·         Material for each unit operation stage is fixed based on the development data (assessment defined in 5.3.2 mandatory and shall be compiled in single report with relevant annexures). Specification of all the materials to be listed with test method references wherever available.

Toxicology Studies:

·         Material and vendor selection performed as per 5.5.1 point number v. Refer table in section 5.6 for requirements for each stage.

·         Details of expiry of all incoming process material documented in Batch Manufacturing Record and COA’s attached to it

·         MSDS understood and to be made available at site of usage for ready reference.

·         Storage and expiry as per vendor recommendation.

·         Compilation of material and vendor documentation in a single report.

DOCUMENTATION DURING DEVELOPMENT AND TOXICOLOGY BATCH MANUFACTURING:

Collection of following documents for all materials (where applicable) as below:

Material Documentation Requirements	Drug Discovery	Toxicology Batch
-   Material Name	ü	ü
-   Material grade	ü	ü
-   Vendor Name	ü	ü
-   Vendors Address	ü	ü
-   Vendor Catalogue Number	ü	ü
-   Vendor Specification	ü	ü
-   Vendor COA	ü	ü (multiple batches)
-   List of potential impurities	ü	ü
-   List of solvents used in process and residual solvents in product, if any	ü	ü
-   MSDS/ SDS	ü	ü
-   Certificate of Material Origin	ü	ü
-   Certificate for TSE/BSE	ü	ü
-   Risk of Viral and other adventitious agents	ü	ü
-   Kosher / HALA certifications	Optional	ü
-   Allergen certificate	Optional	ü
-   Aflatoxin certificates	Optional	ü
-   Certification/ accreditations of vendor	Optional	ü
-   Manufacturing Process Flow	Optional	ü
-   Characterization Data	Optional	ü
-   Toxicological data	Optional	ü
-   Logistic mapping and supply change map	Optional	ü

Note: Material control strategy for clinical and commercial manufacturing are part of corporate/global systems, however for the sake for clarity highlights of material control strategy for subsequent stages of product life cycle are listed below:

Ø  Clinical Phase 1 / 2 Manufacturing:

-   Identification of CMA and preparation of material control specification

-   Development of non compendial test methods

-   Verification of vendor COA for received material against specifications

-   Testing and release of material for parameters such as identification, appearance, safety (bioburden, endotoxin etc) and identified CMA. Availability of approved test methods for these attributes.

-   Vendor qualification for material traceability, supply security with logistic mapping

Ø  Clinical Phase 3 Manufacturing:

-   Material (customer) specification finalization with all CMA listed

-   Availability of test methods for verification of all listed specification parameters for materials.

-   Testing and release of material as per customers’ specification. Full testing for all critical materials.

-   Test values vs material attributes (as per specification) to be trended for better material control as per QMS requirements

-   Risk assessment to be revisited for all critical materials.

-   Due diligence and vendor audits to be performed based on risk assessment.

-   Detailed vendor assessment and qualification.

-   Quality agreements, supply security agreements to be executed and made available.

Ø  Marketing (including PPQ) and Post Marketing:

-   Material to be qualified and trends for high critical tests for critical materials made available. Specifications can be revisited for better control.

-   Vendors to be audited and compliance ensured. All agreements in place.

-   Alternate vendor development can be initiated.

-   Risk assessment based reduced testing can be explored.

DEFINITIONS

Active Pharmaceutical Ingredient (API) (or Drug Substance): Any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body. (Reference ICH Q7).

API Starting Material: A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. API starting materials are normally of defined chemical properties and structure. (Reference ICH Q7).

Contamination: The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or onto a raw material, intermediate, or API during production, sampling, packaging, or repackaging, storage or transport. (Reference ICH Q7)

Control Strategy: A planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (Reference ICH Q10)

Critical Material Attribute: A physical, chemical, biological or microbiological property or characteristic of an input material that should be within an appropriate limit, range, or distribution to ensure the desired quality of output material. (Reference Raw Materials in the Manufacture of Biotechnology Products: Regulatory Considerations Ruth Cordoba-Rodriguez of the FDA’s Center for Drug Evaluation and Research (CDER in Bethesda, MD)

Excipient: Substances other than the API that have been appropriately evaluated for safety and are intentionally included in a drug delivery system. (Reference: USP <1078>)

Impurity: Any component present in the intermediate or API that is not the desired entity. (Reference ICH Q7)

Lifecycle: All phases in the life of a product from the initial development through marketing until the product’s discontinuation (Reference ICH Q8)

Raw material: Any element or component used in the manufacture of a biotechnology product that comes in contact with the API or the API starting material. A raw material can be reactive or non-reactive with the API. (Reference Raw Materials in the Manufacture of Biotechnology Products: Regulatory Considerations Ruth Cordoba-Rodriguez of the FDA’s Center for Drug Evaluation and Research (CDER in Bethesda, MD)

Materials: A general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or APIs. (Reference ICH Q7)

Starting material for biological medicinal products: Any substance of biological origin such as micro-organisms, organs and tissues of either plant or animal origin, cells or fluids (including blood or plasma) of human or animal origin, and biotechnological cell constructs (cell substrates, whether they are recombinant or not, including primary cells).” (Reference Dir. 2001/83/EC)

Biological starting materials: starting materials derived from a biological source that mark the beginning of the manufacturing process of a drug, as described in a marketing authorization or licence application, and from which the active ingredient is derived either directly (for example, plasma derivatives, ascitic fluid and bovine lung) or indirectly (for example, cell substrates, host/ vector production cells, eggs and viral strains). (WHO TRS 999, Annex 2)

REFERENCES:

BioProcess International September 2009: Raw Material Control Strategies for Bioprocesses by Gregory Beck, Mark Schenerman, John Dougherty, Ruth Cordoba-Rodriguez, Christopher Joneckis, Anthony Mire-Sluis, and Lorna D. McLeod.

EBE Concept Paper: Management and Control of Raw Materials Used in the Manufacture of Biological Medicinal Products,  29 November 2017, Version 1.

European Journal of Pharmaceutical Sciences, 2015: Pharmaceutical excipients — quality, regulatory and biopharmaceutical considerations. David P. Elder, Martin Kuentz, René Holm.

Dir. 2001/83/EC: Directive 2001/83/EC of The European Parliament and of the Council. The Community Code Relating To Medicinal Products For Human Use.

EP 5.2.12: Raw materials of biological origin for the production of cell-based and gene therapy medicinal products.

ICH Q5B: Quality of Biotechnological Products: Analysis of the expression Construct in Cells used for Production of r-DNA Derived Protein Products.

ICH Q5D: Derivation and Characterisation of Cell Substrates Used for Production of Biotechnological/Biological Products.

ICH Q10: Pharmaceutical Quality System.

ICH Q11: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/ Biological Entities).

ICH Q7: Good Manufacturing Practice.

ICH Q8 Pharmaceutical Development.

ICH Q9: Quality Risk Management.

IPEC Europe, 2008: Qualification of Excipients for Pharmaceutical Use.

PDA TR 56 (Revised 2016): Application of Phase-Appropriate Quality System and cGMP to the Development of Therapeutic Protein Drug Substances (API of Biological Active Substance).

USP 1078: Good Manufacturing Practices for Bulk Pharmaceutical Excipients.

WHO TRS 999, Annex 2: WHO good manufacturing practices for biological products.

https://www.pda.org/docs/default-source/website-document-library/scientific-and-regulatory-affairs/pcmo-dossier-v5.pdf?sfvrsn=4