Proposed Validation Standard VS-1: Nonaseptic Pharmaceutical Processes

I. Policy Statements

POL 1.1
Every manufacturing process used for producing an Active Pharmaceutical Ingredient (API)*, a critical Intermediate*, a Drug Product*, or In-Process Material* shall be validated.

POL 1.2
Primary Process Validation* administrative responsibility shall be assigned to a Site Validation Steering Committee (SVSC)*, which must minimally include representation by the site Quality Authority* and the site Production Authority*. The SVSC shall adjudicate validation issues and appoint project-specific validation teams as needed that include principal(s) having expertise in the processes involved. Such SVSC responsibilities extend to processes used by contract vendors and suppliers of the firm's drug products and/or APIs, as well as to those processes employed on-site.

POL 1.3
The validation life cycle of a new process involves the following steps:

1.3.1 Define each module (step, unit operation) of the process.
1.3.2 Define Critical Product Specifications*.
1.3.3 Define the Critical Process Operating Parameters*.
1.3.4 Develop the Critical Process Operating Parameter Ranges,* based initially on laboratory studies of manufacturing material behavior under normal and stress conditions, and later on results of producing products under varied conditions.
1.3.5 Define the Probable Adverse Consequences* of exceeding the critical process operating parameter ranges in each direction (end values).
1.3.6 Implement comprehensive Change Control* and Revalidation* procedures.
1.3.7 Qualify equipment (Installation Qualification* and Operational Qualification*).
1.3.8 Train and qualify operational and supervisory laboratory and plant personnel in product-specific validation principles.
1.3.9 Ensure that interrelated systems (e.g., LIMS, environmental controls, utilities) are all validated
1.3.10 Conduct Performance Qualification*.
1.3.11 Assemble and document evidence of process robustness* and reproducibility.
1.3.12 Provide for retention of archived validation files for required periods following last commercial lot expiration date.

A validation life cycle for an established (legacy) or altered process (requires revalidation) will be the same as above, except for those steps that apply and can be shown by Retrospective Process Validation* to have been already satisfactorily completed.

POL 1.4
A Validation Master Plan (VMP)* shall be used to define and coordinate validation activities related to any new, existing, or revised production process.

POL 1.5
Validation Protocols* shall be used to define individual validation experiments and practices.

POL 1.6
Validation Task Reports* shall be used for documenting and summarizing results of validation studies. Definitive statements must be used, especially in describing objectives, conclusions, and product or process definitions. Collectively, project validation task reports are to support acceptability of all critical process operating parameter ranges, corresponding acceptance limits, and evidence of process robustness and reproducibility.

POL 1.7
All validation master plans, protocols, and task reports must be approved and available to the SVSC. All such validation documents created on-site must be approved by the site quality authority and, when production is involved, also by the site production authority.

POL 1.8
Concurrent Process Validation* techniques can be employed only with site management approval, in such exceptional cases as rework lots or orphan drug products.

POL 1.9
When a secondary manufacturing site is scheduled to produce with an established process using similar equipment, the primary site SVSC shall make the necessary process validation information, including the primary site validation task reports, available for use by the secondary site SVSC in preparing its VMP. The new VMP must then also include all site-specific information required to comply with these standards.

POL 1.10
Relevant process validation information from other divisions, departments, and production sites (including R&D) is to be gathered, used, and maintained by the SVSC.

II. Procedural Statements

PROC – 1.a [ref. POL-1.3.1 - 1.3.4]
Process definitions for validation purposes are to be based on the manufacturing master-instruction for APIs and the Dosage Form Monograph (DFM) for drug products. Such definitions are to also include at least the following information:

  • Process flow diagrams where multiple steps are involved
  • Copy of, or reference to, regulatory and operating manufacturing instructions
  • Regulatory and operating acceptance criteria for in-process control tests
  • Regulatory and operating acceptance criteria for critical product characteristics of relevant APIs, drug products, intermediates, and in-process materials
  • A list of all critical process operating parameters
  • Regulatory and internal acceptability limits for each critical process operating parameter range
  • Identification of probable adverse consequences to be expected when acceptable critical process operating parameter ranges are not met.

PROC – 1.b [ref. POL-1.3.1- 1.3.11]
Documented evidence of process robustness shall be established prior to approval of the first production batch*/lot*, and such evidence shall continue to be recorded and analyzed throughout the commercial life of the process and product.

PROC – 1.c [ref. POL-1.3.4]
Small-scale development studies and laboratory experiments must precede plant-scale process validation studies. Documented results of the studies and experiments shall be collected through technology transfer processes, reviewed, and included or referenced in the VMP. Such studies are to include at least the following:

  1. Comprehensive process and product definitions, as listed in POLs 1.3.1-1.3.5
  2. Developmental Pharmaceutics* and other preformulation studies conducted with the drug substance and relevant excipients
  3. Required analytical test methods and controls, including associated validation documentation
  4. Summaries of all pertinent process development and clinical supply batches produced prior to final scale-up
  5. Summaries of pertinent control laboratory work-to-date.

PROC – 1.d [ref. POL-1.3.6]
Change control and revalidation measures shall be established and implemented to identify, document, and review changes to all variables that could alter the validated state of each manufacturing process.

PROC – 1.e [ref. POL-1.3.6]
Change control and revalidation measures include, and are not limited to, review of changes to the following:

  • Product and manufacturing material specifications
  • Source of components
  • Product formula (drug products)
  • Manufacturing process instructions
  • Test procedures
  • Equipment (automated and nonautomated)
  • Support systems, including SOPs
  • Manufacturing location
  • Utilities.

PROC – 1.f [ref. POL-1.3.6]
Results of annual record reviews of product complaints, adverse events, batch records, change controls, revised SOPs, and QA investigations are to be reviewed, analyzed for trends, and responded to as part of the ongoing change control and revalidation programs.

PROC – 1.g [ref. POL-1.3.7]
Installation Qualification (IQ) and Operational Qualification (OQ) are to be conducted and documented in a manner that ensures proper installation and functionality of all processing equipment and permits effective change control.

PROC – 1.h [ref. POL-1.3.7]
Installation Qualification is to include at least the following:

  • List of all equipment, operation of which has potential bearing on product quality or process performance
  • As-built drawings and specifications for all purchased equipment, new or used
  • Verification that all such equipment and the installation thereof meets original intent, including applicable building, electrical, plumbing, and other such codes
  • Preventive maintenance plans and schedules for all such equipment.

PROC – 1.i [ref. POL-1.3.7]
Operational qualification is to include at least the following:

  • A list identifying each module (step, unit operation, or stage) of the process
  • Process operating parameters for each module, including those designated as critical
  • An OQ protocol designed to demonstrate the equipment used in each module operates as intended throughout each process operating parameter range
  • Task report(s) describing the successful execution of each OQ protocol.

PROC – 1.j [ref. POL-1.3.10]
Performance Qualification (PQ)* shall be performed when the following steps are complete and production has been authorized. At least three consecutive, commercial scale lots shall be successfully produced and tested prior to market distribution of any product.

  • Process fully defined, including definition of critical process operating parameters, potential adverse consequences, and critical process operating parameter ranges
  • Product specifications completed
  • IQ and OQ steps completed
  • Operating personnel trained and qualified
  • Change control procedures in place.

PROC – 1.k [ref. POLs - 1.3.3; -1.4]
Critical process operating parameter data shall be collected for each commercial batch manufactured to provide ongoing evidence of process capability and robustness. Tabulations of data (e.g., spreadsheets) shall be maintained and periodically analyzed to ascertain that critical process operating parameter ranges are being consistently met.

PROC – 1.l [ref. POL-1.4]
The Validation Master Plan (VMP) is to include or identify at least the following (to avoid excessive detail in the VMP, cross references to relevant detailed documents may be used, including to validation protocols):

  1. The plan for establishing process robustness, including use of results from development pharmaceutics and other process development efforts, such as the number and sizes of PQ batches intended to be involved
  2. Relevant task reports (e.g., from R&D or other sites)
  3. Identification of all test methods and analytical instruments to be used in the validation work, including calibration plans associated with each
  4. IQ and OQ plans with identification of specific areas in which IQ and OQ are expected to overlap
  5. Individual validation protocols for each validation study
  6. Sampling and testing plans
  7. Provisions for change control and document control to be executed throughout the validation project
  8. Key SOPs and policies
  9. Project team organization with training backgrounds, responsibilities, and authorities
  10. Definition of resources required and allocated
  11. Validation schedules, including responsible party or parties associated with each line item.

PROC – 1.m [ref. POL-1.5]
Each Validation Protocol shall include, and is not limited to, the following:

  1. Statement of experimental objectives
  2. Definition of what is to be qualified or validated
  3. Experimental plan to be executed, including number of trials and data to be gathered
  4. Detailed sampling plans, including sample sizes, sites, and methods
  5. Test plans with acceptance criteria to be met or established
  6. Descriptions of all testing instruments to be used and specific calibration plans (full details or reference to detailed instructions) for each
  7. Description of all statistical analyses to be applied.

PROC – 1.n [ref. POL-1.6]
Validation task reports shall be used for documenting and summarizing results of validation studies. Five illustrative categories of task reports are listed and are not necessarily all-inclusive. Collectively, the validation task reports must support acceptability of all critical process operating parameter ranges, corresponding acceptance limits, and evidence of process robustness:

  1. Product development summary (e.g., as one of several technology transfer measures)
  2. Lot summary report (e.g., identification and size of development and production lots, yields, failures if any, major conclusions)
  3. Process performance report (e.g., tables detailing lots versus actual critical process parameter data)
  4. In-process control report (e.g., tables detailing lots tested versus results, including actual product attribute data)
  5. Validation protocol completion report (could cover any subject for which a protocol is executed).

III. Acronyms

API—Active Pharmaceutical Ingredient
BP—British Pharmacopoeia
BPC—Bulk Pharmaceutical Chemical
cGMPs—Current Good Manufacturing Practice (U.S.)
DFM—Dosage Form Monograph
EC—European Community (now, EU)
EMA—European Agency for the Evaluation of Medicinal Products
EU—European Union
FDA—Food & Drug Administration (U.S.)
GAMP—Good Automated Manufacturing Practice (Forum)
GHTF—Global Harmonization Task Force
IEEE—Institute of Electronic and Electrical Engineers
IQ—Installation Qualification
IVT/SC—Institute of Validation Technology/Standards Committee
NDA—New Drug Application
OQ—Operational Qualification
PAI—Pre-Approval Inspection
PDA—Parenteral Drug Association
PIC—Pharmaceutical Inspection Convention
PMA—Pharmaceutical Manufacturers Association (now Pharmaceutical Research and Manufacturers of America [PhRMA])
PQ—Performance Qualification
QA—Quality Assurance
R&D—Research & Development
SOP—Standard Operating Procedure
SPC—Statistical Process Control
SVSC—Site Validation Steering Committee
USP—United States Pharmacopoeia
VAC—Validation Advisory Committee
VMP—Validation Master Plan

IV. Glossary


Active Pharmaceutical Ingredient (API)—(synonymous with drug substance and bulk pharmaceutical chemical.) A substance that is represented for use in a drug and, when used in the manufacturing, processing, or packaging of a drug, becomes an active ingredient or a finished drug product. Such substances are intended to furnish pharmacological activity or other direct effects in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure and function of the body of humans or other animals.

Batch—A specific quantity of a drug product, an intermediate, an API, or other material that is intended to have uniform character and quality within specified limits and produced according to a single manufacturing order during the same cycle of manufacture.

(Note: see also Lot.)

POL 1.3.6
Change Control—A procedure for:

(a) Identifying all modifications or alterations that are potentially significant to a state of control, qualification, or validation
(b) implementing corrective action, such as repair, readjustment, requalification, and/or revalidation
(c) implementing interim measures to be taken until effective corrective actions are complete
(d) documenting all of the above.

Concurrent Process Validation—a subset of prospective validation in which batches are released for distribution based on extensive testing and data generated during actual implementation of the process. Used only in special cases and with approval of the quality authority.

Critical Process Operating Parameter—an operating variable that is assigned a required control range with acceptability limits, outside of which exists potential for product or process failure. A critical process operating parameter is determined via process development and investigational work.

Critical Process Operating Parameter Range—a range of values for a critical process operating parameter that lie statistically at or below a specified maximum value and/or at or above a specified minimum operating value.

Critical Product Specifications—limitations assigned to specific product characteristics, control of which is important to product safety, efficacy, or other significant fitness-for-use product attributes.

Developmental Pharmaceutics—preformulation studies of the physical, chemical, and (possibly) morphological properties of a drug substance (API) and its interactions with other excipients to be used in a pharmaceutical drug product formulation. Objectives are to provide predictive information leading to a robust product and process.

Drug Product—a finished dosage form (e.g., tablet, capsule) that contains an API, generally in association with excipients. Synonymous with finished drug product.

In-Process Material (as applied to drug product manufacture)—any material manufactured, blended, compacted, coated, granulated, encapsulated, tableted, or otherwise processed that is produced for and used in the preparation of a drug product. (Corresponding materials used in the preparation of APIs are referred to as intermediates.)

Installation Qualification (IQ)—documented verification that equipment, system, or subsystem has been properly installed and adheres to applicable codes and approved design intentions and that supplier recommendations have been suitably addressed.

Intermediate—a material produced during steps in the synthesis of an API that must undergo further molecular change or processing before it becomes an API. The degree to which a given intermediate should be rated "critical" must be determined by a firm's experts based on such criteria as:

  • potential toxicity or other physiological activity
  • degree to which equipment used is dedicated to the process, as opposed to having multiple uses
  • ease or difficulty of removing process residuals when cleaning equipment.

(Note that the term "intermediate" is also occasionally used in relation to certain drug products in regulatory documents.)

Lot—a batch or a specific identified portion of a batch having uniform character and quality within specified limits.

Lot (for an API produced by continuous process)—a specific, identified amount produced in a unit of time or quantity in a manner that ensures its having uniform character and quality within specified limits.

Note: Although lot and batch are considered synonymous, "lot" is often used with packaged APIs or drug products and with purchased raw materials and packaging materials. "Batch" is commonly used for intermediates and in-process materials.

Operational Qualification (OQ)—documented verification that equipment, system, or process performs as specified throughout representative or anticipated operating ranges. OQ frequently includes investigational work and statistical analysis for reduction of nonrandom variation and optimization. (Note: Overlap between IQ and OQ often occurs and is considered allowable, but should be addressed in the VMP.)

Performance Qualification (PQ)—documented evidence that each step in the defined process or system functions as intended and produces intended results under normal operating conditions.

Probable Adverse Consequence—most likely potential failure(s) that will occur to product quality attribute(s) or to process state of control by exceeding a specified control parameter range (in either direction.)

Process Robustness—degree to which a process can function in a state of control under normal plant operating conditions, at commercial scale, with reproducibility from batch to batch.

Process Validation—establishing documented evidence, which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics. Process validation involves activities that start early in the process development life cycle and continues throughout the commercial life of the product.

POL -1.2
Production Authority—counterpart of quality authority, sometimes referred to as production head or, in the case of FLP (Fill-Label-Pack) operations, packaging head.

Protocol—a written plan of action designed to gather documented evidence that will support or refute a set of stated premises or meet predetermined objectives.

Quality Authority—one or more persons who, collectively, have formal responsibilities for specified quality-related operations, such as approval of manufacturing materials, release of finished products, review and approval of documents, and adjudication of quality assurance investigations. titles of quality authority principals vary throughout the world; for example, in the U.S., one term "the q.c. unit," is all-embracing; in the E.U. and Canada, the head of quality control has some of the responsibilities, while a qualified person has others; terms such as responsible head (or person) and quality assurance (and/or control) department are also used in other areas.

Retrospective Process Validation—using historical data, such as batch records and trend analyses, to provide or augment documented evidence that a process does what it purports to do and is stable. (Note: Some regulatory agencies define the term to mean validating the process after the product has been commercialized.)

Revalidation—repetition of the validation process or a specific portion of it. Revalidation may include a total process review and/or requalification of those portions of the process potentially affected by a change.

Site Validation Steering Committee (SVSC)—a standing committee with authority and responsibilities for validation policies, practices, and adjudication of issues. Must include quality authority and production authority representation, and often includes representatives of other involved disciplines. The name of the SVSC may vary from firm to firm.

Validation Master Plan (VMP)—a comprehensive, project-oriented action plan that includes or references all protocols, key SOPs and policies, existing validation task reports, and other relevant materials on which the specific system or process validation effort will be based. The Plan also identifies resources to be allocated, specific personnel training and qualification requirements of relevant, organizational structure and responsibilities of the validation team, and planned schedules. The VMP is subject to periodic revisions covered by change-control procedures.

Validation Protocol—a written plan of action designed to gather documented evidence that will support or refute a set of stated validation premises or meet predetermined validation objectives. (See Protocol.)

Validation Task Report—a written report that summarizes results and conclusions of executing all or any portion of a Validation Master Plan (often referred to as a final report if summarizing all activities of the VMP.)

V. Regulatory Excerpts

When any new master formula and processing instruction is adopted, steps should be taken to demonstrate and document that…the defined process…will consistently yield a product of the required quality.

From time to time, processes and procedures should undergo critical appraisal to ensure that they remain capable of achieving the intended results…

…Repeat studies should be undertaken periodically and in any case whenever a significant change in starting materials or method of manufacture is introduced. Records of validation should be available for inspection.

…the quality assurance or quality control department should…carry out, coordinate or participate in initial and periodic process validation studies

[W]ritten procedures, prepared by qualified personnel [shall] ensure…the drug will meet… specifications…and each lot or batch of that drug shall be produced in compliance with those procedures.

2. All critical production processes are validated.
3. Validation studies are conducted in accordance with predefined protocols. A written report summarizing recorded results and conclusions is…evaluated, approved and maintained.

…No lot or batch of a drug shall be reprocessed without the approval of the person in charge of the quality control department.

6. …Validation of reprocessing operations is required to demonstrate that the quality of the finished product is not affected.

1.3. [GMP requires]:
ii. critical steps of manufacturing processes and significant changes to the process are validated…

4.26. There should be written procedures and... associated records of actions taken or conclusions reached…for…validation…

5.22. [A]ny new manufacturing formula or method of preparation…should…(be suitable) for routine processing [which] should…yield a product consistently of…required quality.

5.23. Significant amendments to…manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process should be validated.

5.37 Critical processes should be validated…

43. Care should be taken that any validation does not compromise the processes.

I Ch.4, Art. 10
[The manufacturer shall]
(l) [Perform validation where]:
A. …drug manufacturing is started at the manufacturing plant.
B. …a change which might cause a serious effect on the quality of the drug is made.
C. Other cases required for the proper conduct of manufacturing control and quality control of drugs.
(2) [R]eport in writing to the product security pharmacist the results of validation.
(3) [R]etain…validation records for three years after the date of recording.

§ 211.110 Sampling and testing of in-process materials and drug products.
(a) …[W]ritten…control procedures shall…validate the performance of …manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product...

…Processes…should…undergo periodic revalidation to ensure that they remain capable of achieving the intended results…

Critical processes should be validated, prospectively or retrospectively.

When any new master formula or method of preparation is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the material and equipment specified, should be shown to yield a product consistently of the required quality.

Significant amendments to the manufacturing process, including any change in equipment or materials that may affect product quality and/or the reproducibility of the process, should be validated.

The efficacy of any new processing procedure should be validated…

Steps that are critical for the quality of the active pharmaceutical ingredient should be defined and the procedures applied should be validated.

Please let us know your thoughts on the proposed validation standard for nonaseptic pharmaceutical processes. It is a proposed standard because we are encouraging industry to offer comments, questions, and recommendations. Your feedback is critical to this standard as well as future standards.

This standard originally appeared in the Journal of Validation Technology.

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